The mature lung has traditionally been assumed to be nonmalleable; structural changes were considered irreversible once normal alveolar development was completed, and treatment for chronic lung disease typically focuses on minimizing symptoms and preventing further tissue destruction. This approach is being revised in light of recent findings. There is growing clinical evidence of accelerated or "catch -up" lung growth in youngsters whose lung disease is no longer active. Several experimental models have shown the possibility of accelerating the rate of lung growth during and beyond the period of postnatal maturation. There has been new insight into the signals, mediators, and anatomic sites of postnatal lung growth as well as their interactions and physiologic correlates. Although much remains unknown, this field is poised on the verge of practical application, with potential therapeutic implications for the management of chronic lung disease, lung volume reduction surgery, and transplantation. This workshop was conducted to summarize relevant recent advances with the objectives of (1) promoting an integrative understanding of the potential for postnatal lung growth that encompasses not just gene expression and cell division, but also the complexities of tissue remodeling, structural interaction, and physiologic function; (2) providing an update on the mechanisms and func tional limits of induced lung growth; and (3) identifying key issues for further investigation.
POSTNATAL LUNG DEVELOPMENT
Alveolarization. Transformation of the immature saccular lung with a limited gas -exchange area to a mature lung with a large internal surface area entails thinning of alveolar walls, growth of capillary network, and extensive subdivision of gas exchange units. This period is marked by interstitial fibroblast proliferation while epithelial cells flatten and decrease in number, resulting in a net thinning of distal airspace walls. Concurrently, alveolar capillary network becomes more complex. Alveolar septation begins as secondary crests that extend from primary alveolar walls. Development of these crests or septae occurs through deposition of new basement membrane, outgrowth of epithelial cells and myofibroblasts at the lips of septae, and elaslin deposi tion (1). In humans, the process begins at approximately 36 weeks of gestation (2). At birth, only approximately 15% of alveoli have formed, with the remaining subdivisions developing in the first few postnatal years (2-5).
Bronchovasculoalveolar interaction. Vascular development occurs via two processes: (1) vasculogenesis, the development of blood vessels from the differentiation of angioblasts in mesoderm, and (2) angiogenesis, classically described as sprouting of blood vessels from existing vessels (6-8), but can also occur by "intussusception" (9), formation and growth of a transcapillary tissue pillar that eventually divides an existing capillary segment into two. The bronchial (systemic) vessels develop with preacinar airways; development is complete by approximately 16 -weeks gestation with further growth in size to match lung growth (3). Bronchial vessels generally are not found in the peripheral acinar region and thus do not normally participate in alveolar gas ex change. Preacinar pulmonary arteries, supplied by the right heart, grow with the airways into the intra -acinar region and fuse with peripheral microvasculature that has arisen from the mesen chyme by vasculogenesis (8). It is not clear whether capillary invasion stimulates alveolar septation or vice versa, but alveolar septation is always associated with capillary invasion. The impor tance of vascular supply to alveolarization is demonstrated by studies using antiangiogenic agents such as fumagillin, thalidomide, and Su-5416, an inhibitor of the vascular endothelial growth factor (VEGF) receptor; these agents disrupt vascular development, leading to reduced pulmonary arterial density and inhibition of alveolar growth (10).
Bronchial arteries are responsive to angiogenic stimuli throughout life. Unilateral pulmonary artery ligation augments growth of bronchial arteries in lambs and mice (11,12). In chronic pulmonary hypertension, bronchial vessels grow even as peripheral pulmonary vessels are lost (13). In lung disease, angiogenesis of the bronchial circulation does not support normal gas exchange, and the high pressure of these systemic vessels can lead to life-threatening hemoptysis. In regions of bronchial angiogenesis, local pulmonary vessels do not show angiogenesis, suggesting that the two vascular systems respond independently (14). There is only limited evidence supporting induced postnatal growth of intra-acinar blood vessels, as after chronic pseudomonas infection in rats (15) and in patients with veno-occlusive disease (16).
Although the lung is extensively innervated from early fetal life, postnatal denervation by cervical vagotomy and sympathectomy does not significantly affect subsequent lung growth or mechanics in growing rats and rabbits (17-19); hence, pattern and extent of growth are not critically dependent on neural control or communication.
Clinical syndromes. Syndromes that alter expression of growth factors, cytokines, transcription factors, or extracellular matrix (ECM) proteins provide models to explore mechanisms that control alveolar development. Signals that regulate the saccularto -alveolar morphologic transition are poorly understood, but disrupting lung septation during this transition impairs alveolar formation, resulting in a loss of alveolar surface area (20, 21). There are several syndromes of abnormal lung alveolarization in humans. Trisomy 21 (Down syndrome) is associated with reduced lung volumes, alveolar surface area, fewer alveoli, defective elastin deposition, and vascular abnormalities (22, 23). Leprechaunism, caused by a defect of the insulin/insulin-like growth factor-I receptor, is associated with reduced lung surface areas as well as fewer and larger alveoli (24). Oligohydramnios (25), congenital diaphragmatic hernia (CDH) (26), and intrathoracic mass lesions are all associated with pulmonary hypoplasia caused by the lack of interplay between thoracic expansion and stretch imposed on the lung. Lung hypoplasia in CDH is not just a consequence of mechanical lung compression caused by a hole in the diaphragm but also involves primary developmental defects (27). Prenatal tracheal occlusion markedly increases lung size in some fetuses with severe CDH; however, survival remains poor because of respiratory insufficiency and prematurity (28). After CDH repair, significant postnatal alveolar growth and vascular remodeling are seen (26); long-term survivors show lower lung volumes but normal airway function and exercise tolerance (29), suggesting the occurrence of "catch-up" lung growth once the underlying abnormalities are corrected.
By far the most common cause of abnormal postnatal human lung development is bronchopulmonary dysplasia (BPD). Classically, BPD occurs in the preterm infant lung exposed to hyperoxia and mechanical ventilation (30-32), resulting in extensive alveolar fibroproliferation, bronchovascular smooth muscle hyperplasia, and inhibition of distal lung formation leading to longterm pulmonary dysfunction persisting into adolescence and adulthood. The advent of antenatal steroids, postnatal surfactant replacement, and improved intensive care has ushered in the "new BPD," which lacks the severe bronchovascular lesions and interstitial fibrosis but is characterized by abnormal lung development with simplified acinar structure, poorly formed secondary crests, dysmorphic alveolar capillaries, and blunted expression of angiogenic growth factors and their receptors (33-36). There is little information on the pathology of "new BPD" in infants who survive; it remains to be seen whether long-term "catch -up" lung growth occurs in these survivors.
MODELS OF INDUCED POSTNATAL LUNG GROWTH
In general, larger species exhibit more mature lungs at birth. Alveolar size is similar among mammals at birth but increases more poslnatally in larger species than in smaller ones, associated with a thicker septal interstitium, which contains more collagen and elastin fibers to bear the force of lung distension (37, 38). Rodents are born with the lung in the saccular stage; alveolarization occurs exclusively from Days 4-14 after birth, followed by alveolar wall thinning between Days 14 -21 (39). Because rodent epiphyses never close (40), thoracic growth and alveolarization persist throughout life (41 ). In comparison, most of the alveoli in guinea pig lungs have already formed at birth (42, 43) containing more septal connective tissue (44) and less pulmonary vascular smooth muscle (45). Guinea pigs also undergo epiphyseal closure beginning at approximately 5 months of age (46), suggesting that older animals reach an upper limit of thoracic and hence lung size. In rabbits, alveoli continue to form after birth into adulthood (36 weeks), but septal thinning occurs mostly before birth (47). Their alveolar blood -gas barrier is thinner with a higher capillary wall stress compared with larger species (dog and horse) (48, 49); septal thickness and capillary wall strength increase with postnatal maturation (50).
There are no major differences between dogs and humans in the characteristics of lung structure or function during postnatal maturation and aging (51). Because they are highly aerobic and easily trained, dogs are used in exercise studies to define the functional correlates of lung growth. Sheep are born with wellformed alveoli; postnatal growth only modestly increases alveolar complexity and total alveolar number (52). Pigs are born with alveolar -capillary surface densities and air-blood tissue barrier thickness already at adult levels (53). Airspace expansion and septal thinning during the first postnatal week increases elastic recoil, followed by vigorous septal subdivision and thickening (54, 55). Lung development in primates closely mimics that in humans, although postnatal alveolar growth in monkeys has been attributed to an increase in alveolar size rather than an increase in number (56). Primates that assume an upright position (the great apes) show an elongated thoracic cross-section in the lateral direction and similar anatomic relationships among lungs, thorax, heart, and diaphragm as humans. Primates that are quadrupeds (monkeys and baboons) have an elongated thoracic cross-section in the anteroposterior direction and an additional infracardiac lung lobe separating the heart from the diaphragm; their mechanical interactions among intrathoracic structures are more similar to that of nonprimate quadrupeds (57). Across mammalian species, adult dimensions of alveolar surface area and diffusing capacity (DL) are directly related to body mass and aerobic capacity (58), indicating an evolutionary match between lung growth and functional demands of the spe cies.
One fundamental difference between prenatal and postnatal lung growth is that prenatal alveolar tissue arises from undifferentiated mesenchyme, whereas postnatal alveolar growth is constrained by an already highly differentiated scaffold. Hence, adaptive strategies may also differ. Strategies that have been attempted to induce postnatal lung growth experimentally are summarized later here and in Table 1.
Increased Metabolic Oxygen Demand
Early observations that champion swimmers possess greater lung volumes and lung DL (59) inspired attempts to stimulate lung growth by increasing chronic O2 flux across the lung via increased metabolic O2 consumption (60-63), leading to conflicting results. Cold exposure modestly increases lung tissue volume, alveolarcapillary surface areas, and DL in rats (62) but not guinea pigs (60). Exercise training does not increase DL in rats (61) or guinea pigs (43, 60). The higher DL in Japanese Waltzing mice (63) is complicated by species differences in lung metabolism, protein synthesis, and pneumocyte mitochondrial characteristics (64). Increasing O2 uptake and DL in hyperthyroiclism may or may not alter lung structure in rats (61, 65). Although metabolic O2 demand and mechanical stress of exercise cause hypertrophy of working muscles, diffusive gas exchange, a passive physical transport across the air-tissue-blood barrier that is primarily determined by the available alveolar-capillary-erythrocyte surface areas and thickness of the diffusion barrier, may not be stressed beyond existing structural capacity.
Increased Mechanical Lung Strain
Mechanical stretch in vitro stimulates fetal rat lung cell prolifera tion (66). Mechanical stresses of fetal breathing movements and fluid tension promote fetal lung development (67). Diminished alveolar wall tension imposed on developing lung is associated with lung hypoplasia (68). Expression of immediate early growth -associated genes c -fos and junB is elevated acutely both in situ and in isolated lungs subjected to distending airway pres sures or increased perfusion (69). Positive pressure lung inflation rapidly induces ECM remodeling in open -chest rabbits by selec tively increasing mRNA levels for a number of procollagens, fibronectin, basic fibroblast growth factor (FGF), and trans forming growth factor (TGF). (70). Application of continuous positive airway pressure increases lung protein and DNA content in weaning ferrets (71). Lobar liquid distention by instillation of perfluorocarbon accelerates lung growth in neonatal but not adult lambs (72). Extensive published data, reviewed by Rannels (73), are consistent with a major regulatory role for mechanical signals in both initiation and progression of normal as well as compensatory lung growth (see MECHANICAL SIGNALS).
A highly robust model of strain -induced lung growth is surgical resection of one or more lobes (lobectomy) or one lung (pneumonectomy), which initiates rapid growth of the remaining lung in mice, rats, rabbits, ferrets, and dogs (74-82) (Figure 1). In rodents after pneumonectomy, various transcription factors are transiently upregulated (83), followed by an accelerated increase in lung weight (84, 85) associated with proportional increases in all major alveolar septal cell populations (86-89), protein and DNA synthesis (78, 87), collagen, and elastin accumulation (90, 91), leading to normalization of alveolar architecture. Whether compensatory growth in rodents normalizes lung function is not clear.
There are important species differences in the postpneumonectomy response. Primitive organisms are more capable of tissue regeneration than higher order complex organisms (92). Among mammals, rodent lung architecture is simpler and physiologic reserves for gas exchange more limited than in larger animals. Somatic growth continues in rats throughout their lifespan (40), and there is no stable final thoracic size. Consequently, in the adult rat, alveolar tissue growth is easily reinitiated after the removal of only one or two lobes (74, 93), and compensatory growth advances more rapidly and completely (90) than in larger adult mammals (94, 95) where the lung and thorax attain a maximum size on epiphyseal closure.
There are also maturity-related differences in the postpneumonectomy response. In immature dogs, accelerated postpneumonectomy growth of the remaining alveolar tissue normalizes total septal tissue volume and resting gas exchange within 8 weeks (96). In adult dogs, compensatory alveolar growth is reinitiated only when the amount of lung resected exceeds a threshold (approximately 50%) (94, 95). Subthreshold resection elicits compensation via recruitment of existing physiologic reserves and remodeling of existing seplal tissue; these mechanisms can adequately maintain arterial O2 saturation up to heavy exercise without the need for new lung tissue growth (94, 97, 98). Above the threshold, both physiologic recruitment and new alveolar tissue growth occur, but functional improvement progresses slowly and never completely normalizing oxygen transport (95, 99). Functional compensation generally lags behind cellular growth. Early after pneumonectomy, the septum thickens as a result of disproportional enlargement of the interstitial compartment (95) without a significant compensatory increase in DL, and arterial hypoxemia develops early during exercise. Subsequently, tissue remodeling occurs with thinning of septa and progressive improvement in DL as well as arterial O2 saturation (99).
Reduced Size (Lobar) Lung Transplant
Reduced-size or lobar transplant, where one lobe instead of a whole lung is transplanted into the recipient's hemithorax, could significantly expand the donor organ pool for treating patients with end -stage lung disease. In children receiving living donor lobar transplants compared with those receiving cadaveric whole lung transplant, lung volume increased but volume -adjusted DL progressively decreased over 6-12 months, suggesting that alveolar dilation, rather than alveolarization, was responsible for the increased lung volume after lobar transplant (100). Other factors such as immunosuppression and infection may influence the growth of the graft and complicate interpretation of the functional data.
In animal studies, mature lobar allografts gradually expand within the growing chest of an immature recipient (101-104); whether the mechanism responsible for this increase in size is alveolarization (lung growth) or simple alveolar dilation is still a matter of debate. In a study comparing lung growth after reduced-size lobar transplant and that after lobectomy (105), the left lung from immature swine was replaced with the left lower lobe from mature swine. Response in the allograft was compared with that in the left lower lobe of the remaining after left upper lobectomy in the mature swine. After lobectomy, the remaining left lower lobe undergoes rapid weight gain by 2 weeks. Weight gain of the transplanted mature lobe is more gradual over 3 months. Alveolar cell proliferation increases markedly 2 weeks after lobectomy, returning to baseline by 3 months, whereas cell proliferation in the allograft increases gradually, reaching significance at 3 months. The slower allograft growth may be related to the available thoracic space; the free space after lobectomy allows the remaining lobe to expand, whereas the allograft fits snugly within the hemithorax and its expansion is limited. The lack of mechanical strain and the presence of ischemia/reperfusion injury associated with transplantation may hinder allograft growth. Functional residual capacity and resting oxygenation did not differ after lobar transplantation or lobectomy (101, 102). Alveolar surface density and architecture are unaltered after lobectomy or transplant. Given the increased lung weight, alveolar number presumably increased in the lobar allograft as in the remaining lung after lobectomy. A study in sheep also concluded that alveolar multiplication occurs in the mature lobe transplanted into the growing thorax of an immature animal (104). However, other studies in rats (103) and minipigs (106) reported predominantly alveolar enlargement in the transplanted lobe.
Chronic Hypoxia or High-altitude Exposure
Chronic hypobaric hypoxia affects approximately 400-million people living above approximately 50 ,0000 ft altitude. Native Tibetan newborns show higher arterial oxygen saturation than Han newborns whose mothers had resided at high altitude for approximately 2 years (107). Whereas somatic growth is slowed and perhaps prolonged at high altitude (108, 109), native highlanders show larger vital capacities and thoracic volumes than lowlanders regardless of ethnic origins (110-116). Where measured, Di. is also increased in native highlanders as well as persons born and raised at sea level who subsequently move to high altitude as adults (116, 117). The adaptive pattern is consistent with highaltitude -enhanced lung growth. A major problem of human population studies at high altitude is a lack of structural data to discern the basis of functional differences. It is unknown whether alveolarcapillary surface and volume have increased by growth or whether the thorax has simply become more compliant allowing the lung to expand to a higher volume. The higher DL could also be due to reversible increases in microvascular pressures, blood volume, and hematocrit instead of induced lung growth.
In vertebrates, hypoxia uniformly causes hypertrophy of gas exchange organs independent of rhythmic stretch of the organ; examples include gills in fish and salamander (118), redundant skin folds in bullfrogs (119), and placenlal hypertrophy in mammals (120). Mice native to high altitude show a greater volume fraction of lung tissue and smaller alveolar volume than the same species living at sea level, attributed to hypertrophy of types I and II pneumocytes and endothelial cells (121); epithelial, endothelial, and erythrocyte surface areas per gram body weight are also greater. Chronic hypoxia initially accelerates lung growth and alveolarization in rats while variably retarding somatic growth (41,122-127). Within 3 weeks of hypoxic exposure, lung volume becomes 20% larger than in normoxic control animals; then the rate of lung growth returns to normal, although the relative increase in volume is retained (128).
Growing rats show maturity-dependent responses to hypoxia (129, 130). Perinatally, even brief hypoxic stress blunts lung development at age 7 days; effects are sustained to 30 days (130). Between 2-14 days of age, hypoxia impairs alveolar septation. However, between 14-40 days, alveolar volume increases less and alveolar number increases more in hypoxic rats than in normoxic rats, suggesting stimulated alveolar growth. Older rats (23 days), raised in normoxia and then exposed to hypoxia, demonstrate greater alveolar surface area and volume than cor responding normoxic control animals, but the alveolar number is unchanged, suggesting alveolar enlargement (129). In addition to hypoxia, exposure to hypobaria (in normoxia) in growing rats may accelerate cellular proliferation and modulate structural lung growth in subtle ways (126, 127, 131, 132). Hypoxia also enhances postpneumonectomy lung growth in rats (133). Unlike humans, pulmonary gas exchange efficiency does not signifi cantly limit O2 transport in rats regardless of altitude (134). These studies are uniformly of short duration and do not address long -term effects. After rats exposed to high altitude return to sea level, their lungs stop growing, whereas the lungs of sea level control animals continue to grow until lung size in the two groups are similar; hence, an increased lung volume at high altitude may not be permanent (135).
Two studies have addressed long -term lung growth at high altitude and reached diverging conclusions (136, 137). In guinea pigs, bony epiphyses close beginning at approximately 20 weeks of age (46). Weanling guinea pigs raised from 2 to 16 weeks of age at simulated extreme altitude (5,100 m) (136) show initially accelerated increase in lung volume and alveolar surface area compared with normoxic control animals in a manner independent of hyperventilation (138). However, the stimulatory effect progressively diminishes with duration of exposure, suggesting that severe hypoxia may not extend the upper limit of alveolar growth at maturity but merely accelerates the rate of its attainment, and the ultimate lung dimension may be determined predominantly by thoracic size. Because both somatic growth and the age of epiphyseal closure tend to be retarded at high altitude (108), lung growth of high-altitude guinea pigs may continue beyond the reported observation period. In contrast, dogs raised from age 2 to 14 months at 3,100 m (137) show significantly larger lung volumes, septal tissue volumes, and DL than matched control animals raised to maturity at sea level; differences persist 9 months after returning to sea level. Results in dogs suggest that hypoxia enhances lung growth during maturation and elevates gas exchange capacity at maturity. The size of rib cage, rib length, and curvature are not altered in dogs raised at high altitude, but the dome of diaphragm moves to a more caudal position at a given transpulmonary pressure to accommodate the larger lungs. Pulmonary vascular reactivity to hypoxia returns to normal, but right ventricular hypertrophy persists 8 months after returning to sea level, suggesting permanent pulmonary vascular structural alterations (139). Differences between responses in guinea pigs and dogs may be related to differences in the severity of hypoxia and the length of observation.
Comparative data provide important clues regarding the interplay between lung and rib cage in determining the final lung size and support the hypothesis of two interacting growth stimuli at high altitude. During normal development, distending pressure generated by the outward recoil of the growing rib cage exerts mechanical traction on alveolar septa, and the resulting tissue tension provides a major signal for cellular lung growth. Growth of the lung relieves tissue tension and allows the rib cage to expand further in a feedback loop that continues until somatic maturity when epiphyseal union occurs (Figure 2). Ultimately, dimensions of the lung and thorax are matched. Hypoxia independently stimulates lung growth but if severe enough may retard rib cage growth. At a moderate altitude, stimulation of lung growth predominates. Space for the expanding lung is provided by passive rib cage expansion and caudal displacement of the diaphragm. At extreme altitudes, inhibition of rib cage growth may predominate; although lung growth is initially stimulated, the effect diminishes with time as lung size becomes limited by the smaller rib cage. At extreme altitude (> 5,000 m), somatic growth is so retarded as to prevent an absolute increase in lung volume, even though volume with respect to body weight is larger than in sea level controls (135) (see LIMITS IMPOSED BY DYSANAPTIC LUNG GROWTH).
EXTRACELLULAR MATRIX AND ELASTIC FIBERS
Association of cells with their basement membrane, ECM proteins and fibers regulates cell survival, proliferation, and differentiation (140-142). Elastin is a chief component of septal interstitium (143, 144). Tropoelastin monomers are assembled and cross-linked on pre-existing fibrillin-containing microfibrillar scaffolds (145). First expressed near airway branch points during the pseudoglandular stage, elastin gene expression peaks during alveolarization when elastin fibers localize to the tips of alveolar secondary crests, forming rings that surround alveolar entrances and deposit in bundles within alveolar walls (144, 146, 147). As elastic fibers are the primary means by which the energy of mechanical stretch is stored and released in the septum, these fibers and the elastin-expressing cells fundamentally determine septal mechanical properties and strain-related signal transduction. The composition of microfibrils and the cellular events that control elastin gene expression, secretion, and assembly are actively under investigation, but little is known of how cells work together to assemble elastic fibers in diverse patterns required for maintaining mechanical integrity of elastic organs.
Alveolar walls have been likened to tents supported by ropes (elastic fibers) and poles, whose lengths and tension largely determine the shape of the tent (148). Mechanical stresses provide signals for the orientation and differentiation of alveolar myofibroblasts as well as directional organization of a complex elastic fiber network. The position, smooth muscle phenotype, and elastin-expressing capacity of alveolar myofibroblasts suggest that they construct, reinforce, and modify elastic fibers to accommodate changing stresses. Intermittent stretching of fetal lung cell in organotypic culture increases tropoelastin gene transcription (149). Elastin expression in alveolar myofibroblasts is upregulated by TGF-[beta] and downregulated by basic FGF (150, 151). Preventing alveolar elastin deposition through inhibition of lysyl oxidase-mediated crosslinking (152, 153), exposure to hyperoxia (154, 155), dexamethasone (20), depletion of alveolar myofibroblasts (156, 157), or targeted ablation of elastin gene (158) all result in enlarged emphysema-like alveoli containing fewer septa. Moreover, there is a link between retinoids (159) and lung elastin (160, 161). A subset of lipid-laden alveolar myofibroblasts metabolizes retinoids (162), which upregulate elastin expression (160). Deletion of retinoic acid receptors leads to reduced lung elastin and alveolar numbers (161). Whether alveolar myofibroblasts are the primary responsive cells in retinoid-enhanced lung development is unclear.
Elastic Fibers in Alveolarization
During transition from the saccular to the alveolar stage, the walls of terminal respiratory units become thinner by apoptosis (163), and a single layer of capillaries replaces the double-capillary network found in rudimentary alveolar walls (164). Later, new septae arise at bends in alveolar walls, effectively increasing gas exchange surface. It is likely that paracrine signals among myofibroblasts, type II pneumocytes, and capillary endothelial cells are necessary for formation and extension of secondary septae. Individual alveolar walls can form free "ends" at the mouths of alveoli, join another alveolar wall at an angle forming "bends," or join with two alveolar walls at a "junction" (148, 165, 166) (Figure 3). Elastic fibers and alveolar myofibroblasts localize to ends and bends where retractive forces develop during inspiration, but not at junctions, which are reinforced with collagen fibers. Bends in alveolar walls have been proposed as sites where new alveolar septae arise and extend. Mechanical stress applied to an elastic fiber running along a bend in an alveolar wall may cause the fiber to pull away from the wall, initiating the formation of a new septum.
If elastic fibers transmit force at bends in alveolar walls during secondary septation, aberrant elastic fibers might contribute to failed seplalion in disease. In the classic BPD, the lung appears "fibrotic," with large consolidated regions and simple, enlarged terminal airspaces (167). In preterm lambs with BPD (168), thickened and tortuous elastic fibers were localized to stubby, malformed alveolar secondary crests. Elastin gene expression continues unchecked in the alveolar walls of BPD lungs, while declining markedly as alveolarization progresses in age-matched gestational control subjects. Human BPD is characterized by increased elastin turnover but a paucity of elastic fibers in alveolar walls (169, 170). However, blocking alveolarization in new-born rats by hyperoxia represses elastin gene expression (143). Divergent observations indicate that altered elastic fiber production and turnover are associated with failed alveolarization, but they do not establish a cause-effect relationship. Nonetheless, it remains likely that altered elastic fiber morphology may contribute to persistence of BPD by altering lung mechanics and posing a barrier to remodeling of the alveolar wall.
Remodeling of Elastic Fibers
Elastin is one of the most durable proteins, with a half-life that can exceed the lifespan of the organism (171). Elastic fibers must be remodeled, expanded, or extended during lung growth. As elastic fibers are insoluble polymers with desmosine crosslinks, remodeling cannot occur by redistributing monomeric tropoelastin. Rather, enzymatic digestion and new synthesis must occur. Elastases include the zinc-binding matrix metalloproteinases (MMP) and serine proteases such as pancreatic elastase and neutrophil elastase. Several of these, including MMP-9, MMP-12, and neutrophil elastase, are implicated in the pathogenesis of emphysema (172, 173). No clear role for these enzymes in lung development and growth has yet been demonstrated by gene targeting, perhaps because of functional redundancy of many MMPs. Specific or broad-based MMP inhibitors may provide another approach to assess the roles of MMPs in latter stages of lung development.
In adult rats after removal of the left lung and accessory lobe, expression of tropoelastin mRNA in the remaining lung was induced by 3 days, peaked at 7 days, and declined by 14 days, when the mass of the remaining lung had doubled (91). Insoluble elastin content measured by desmosine increased in parallel with lung growth. Postpneumonectomy expression of tropoelastin mRNA localizes to myofibroblasts in alveolar walls at sites similar to those found during normal postnatal alveolarization, leasing to suggestions that similar signals might drive both developmental and induced lung growth.
Other matrix proteins, such as fibronection, are also present throughout developing lung mesenchyme (174, 175) and at tips of secondary septae in the alveolar stage (176). Via binding to integrin receptors and formation of cell-matrix adhesions, fibronectin is essential for initiating cleft formation during epithelial branching (175) and for the migration, proliferation, differentiation, and apoptosis of various cells during organogenesis (174). The mechanisms and significance of its role during post-natal reinduction of lung growth remain poorly understood.
SIGNALS AND MEDIATORS OF INDUCED LUNG GROWTH
Septal strain. After reaching somatic maturation, the thorax attains a maximum size, and lung strain stabilizes so that a larger increase in mechanical strain must be imposed before alveolar growth is reinitiated in the adult animal. After pneumonectomy when the resected lung is replaced by a space-occupying plombage or prosthesis to prevent mediastinal shift and mechanical lung strain in mice (87), rats (177), ferrets (81), rabbits (178), and dogs (179, 180), growth of the remaining lung is blunted, but compensatory increases in DL, septal tissue volume (179), or DNA synthesis (87) are not totally eliminated. Instead of expanding laterally across the midline, the remaining lung changes shape and enlarges modestly in the caudal direction via expansion of the ipsilateral rib cage and displacement of the hemidiaphragm (178, 179). Hence, other signals, perhaps endothelial distention and shear or nonmechanical factors, are also implicated in growth reinitiation and progression. Delayed reinstitution of lung strain after deflation of the prosthesis weeks to months after pneumonectomy leads to progressive expansion of the remaining lung and a vigorous tissue response (81, 179, 180).
Capillary distension and shear. Ligation of one pulmonary artery increases perfusion to and augments alveolar growth of the contralateral lung in newborn pig (181). After pneumonectomy, pulmonary perfusion per unit of remaining lung tissue doubles. Typically, pulmonary arterial pressure is normal at rest but elevated on exercise (182-184). Pulmonary capillary blood volume per unit of remaining lung tissue is increased (185). Chronic capillary distention and increased shear forces could contribute to endothelial cell growth and septal remodeling but have not been thoroughly investigated. In postpneumonectomy ferrets, restricting blood flow to the remaining lung by banding one lobar pulmonary artery has no effect on the compensatory increase in DNA and protein content of the banded or unhanded lobe (186).
To understand how alveolar capillaries adapt to mechanical stress, we need to refer to models of sustained alveolar-capillary distension and congestion, including chronic heart failure (CHF) and pulmonary venous hypertension where alveolar-capillary pressure is elevated both at rest and during exercise (187, 188). Whereas CHF increases transendothelial water flux in lungs (189-191), interstitial or alveolar edema does not always develop (192-194). This adaptive response involves structural remodeling of the alveolar-capillary barrier, septal interstitium, extra-alveolar pulmonary vasculature, as well as functional remodeling of signaling pathways regulating endothelial barrier function. Thickening of the endothelium and epithelium of the alveolar-capillary barrier occurs within 1 month of pacing-induced CHF, whereas remodeling of the basement membrane takes longer (195, 196). Within 5 months of left ventricular failure caused by aortic banding, there is marked thickening of the alveolar septum as well as basement membrane (195). Although no report has specifically addressed the progression of septal remodeling in humans, thickening of the septal barrier and basement membrane has been observed in mitral stenosis (197). Septal remodeling in response to chronic capillary congestion serves a protective role by raising the pressure required to induce stress failure of the blood-gas barrier (48, 196, 198). Despite early thickening of the septal barrier and increased resistance to stress failure, basal endothelial permeability remains normal (192, 196, 199), and the endothelium is refractory to injury (200) after 1-2 months of pacing-induced CHF. The more extensive alveolar septal remodeling seen in the aortic banding model is actually associated with decreased endothelial permeability (195). On the other hand, remodeling of the blood-gas barrier can also be maladaptive by decreasing DL and exercise tolerance as in patients with CHF (201, 202).
Remodeling of extra-alveolar resistance network lags temporally behind alveolar septal remodeling. In pacing-induced failure, there are no structural changes in small extra-alveolar arteries or veins up to approximately 500 µm in diameter (203). Within 4-5 months of CHF, medial hypertrophy develops in resistance microvessels (195) and pulmonary artery (204). In patients with CHF, the decrement in DL correlates with the increase in pulmonary vascular resistance (202). Postmortem histology of lungs from patients with long-standing pulmonary venous hypertension also shows significant remodeling of extraalveolar pulmonary vasculature (205).
Acute interstitial edema increases synthesis and deposition of collagen and glycosaminoglycans in the lung, which are known determinants of the interstitial pressure-fluid volume relationship (206-208). However, chronic pulmonary capillary congestion alters the interstitial pressure-fluid volume relationship in a way that maintains a normal interstitial fluid pressure in the face of lung edema and does not change the lung content of glycosaminoglycans, hyaluronan, or collagen relative to blood-free dry mass (203). However, because blood-free dry lung mass increases significantly in CHF (192, 199, 200, 209), matrix deposition likely also increases. In acute lung injury or pulmonary fibrosis, glycosaminoglycan deposition precedes deposition of mature collagen; myofibroblasts in regions of increased glycosaminoglycan deposition also contain type I procollagen (210). Dilated cardiomyopathy is associated with increased plasma levels of type III collagen propeptide, the 7S domain of type IV collagen, laminin, and type I collagen telopeptide (211, 212), which can be attributed to increased matrix turnover in the heart, lung, and liver.
Mechanical alveolar capillary strain stimulates matrix synthesis in lung fibroblasts (213), and acute pulmonary venous hypertension increases mRNA expression for types I and III procollagens, laminin, and fibronectin in lung parenchyma (214). Increased synthesis of matrix proteins in either septal interstitium or extra-alveolar vessel walls may not result in increased net deposition if degradative pathways are concomitantly stimulated. Acute hydrostatic pulmonary edema increases parenchymal activity of MMP-2 and MMP-9 (215), which is known to mediate pulmonary vascular remodeling (216); similar upregulation is seen in CHF. In experimental pulmonary arterial hypertension, endothelial injury stimulates rapidly progressing matrix synthesis and medial hypertrophy (217). The lack of early endothelial injury in CHF likely contributes to a relatively slow time course of vascular remodeling and pulmonary venous hypertension. These models can offer important clues as to how remodeling occurs within alveolar septa in response to capillary congestion. However, other effects of CHF such as neurohormonal alterations complicate the picture and preclude a clear separation of the mechanical signals from nonmechanical signals acting on the alveolar capillary bed.
Strain-induced signal transduction. Transduction of mechanical signals within and between cells is mediated via cytoskeletal proteins, integrins, and various cell-cell adhesion molecules (218-222). At focal adhesions sites, cell membranes and their underlying substratum are physically connected via integrins that bind specifically to the Arg-Gly-Asp amino acid sequence in ECM proteins (223). The cytoplasmic tails of integrins may bind to the actin cytoskeleton via several structural linking proteins, including talin, vinculin, and paxillin (224). Techniques such as magnetic twisting cytometry (225, 226), where ferromagnetic microbeads are bound to specific cell surface integrins, have been used to probe effects of mechanical deformation on individual cells. Stressing integrin receptors enhances tyrosine phosphorylation of cytoskeletally anchored proteins (227) and activates the cAMP cascade (228). Twisting Arg-Gly-Asp-coated beads bound to human endothelial cells more than doubles endothelin-1 gene expression, whereas twisting nonadhesion molecules does not alter endothelin-1 gene expression (229).
Intracellular mechanotransduction is mediated via the cytoskeleton, a discrete, tensed network that enables adherent cells to resist distortion and regulate cell shape, polarity, locomotion, growth, signal transduction, gene expression, as well as protein synthesis (225, 230-232). The concept of "tensegrity" (tensional integrity), exemplified by Fuller's geodesic dome (233), has been applied to tissue and cytoskeletal mechanics (234-236). Tensegrity structures are envisioned as a network of support elements that interact under continuous tension to resist mechanical deformation; after external loading, elements reorient themselves to achieve a new equilibrium to reduce distortion (Figure 4). The concept broadly applies to all size scales and provides one explanation of how localized mechanical stresses elicit distant biochemical responses. Tensegrity structures require prestress (preexisting tension before external loading) to maintain stability of a given shape; when prestress approaches zero, the structures collapse. Within the cell, prestress is generated actively by the actomyosin apparatus and passively by traction at the cell-ECM interface; these forces are carried by actin microfilaments and intermediate filaments and stabilized via adhesions to the ECM. As prestress increases, cells become suffer and resist further distortion. A measure of tissue or cell resistance to distortion is the shear stiffness (or elastic modulus, the ratio of shear stress to shear strain), which increases directly with prestress or distending force. Thus, stiffness of cultured cells increases with contractile agonists and decreases with relaxing agents in a dose-dependent manner (235, 237-239). Cell stiffness also increases with biaxial stretch (240), supporting the role of prestress in determining the stability of cell shape.
At a given level of growth factor stimulation, the stability of cell shape and the extent of cell spreading are the key factors controlling cell growth and apoptosis in vitro (241). Cell tension increases as cell spreading is promoted (242). Restricting the shape and spreading of cultured capillary endothelial cells suppress growth and induces apoptosis (241). In cultured fibroblasts, mechanical strain stimulates connective tissue synthesis, inhibits matrix degradation, and increases growth factor gene expression in a manner dependent on the type of strain as well as mechanical interaction with the substratum (243). Normal cells grown on flexible substrates show decreased DNA synthesis and increased apoptosis associated with lower cell spreading area and traction forces compared with cells cultured on identical but stiff substrates (244). In contrast, oncogenically transformed cells lose the normal mechanical feedback and maintain their growth and apoptosis rates regardless of substrate flexibility, highlighting the importance of mechanical cell-ECM interaction in regulating cell growth. Although the material properties of purified cyloskeletal filaments or reconstituted cytoskeletal gels are known, it remains unclear how the mechanical feedback response of intact cells emerges from collective interactions of individual components. Dramatic changes in tissue force balance as occurs after pneumonectomy or with continuous positive airway pressure must alter the distribution of, and response to, cell prestress; this pertubation has yet to be delineated but likely regulates subsequent biochemical and molecular events in important ways.
Nonmechanical Signals and Mediators
Hormones. Early interests were spurred by studies of patients with acromegaly who demonstrate partially reversible increases in lung volume and distensibility but normal DL per unit lung volume (245-248); supranormal lung tissue volume is seen in some but not all patients (245). Functional measurements were done at rest, and thus, it is unclear whether DL could increase to a greater extent during exercise in acromegalic patients. Administering excess growth hormone to young adult rats accelerates body growth with proportional increases in lung volume and alveolar surface area (249), suggesting that excess growth hormone primarily enhances growth of rib cage without specific stimulation of alveolar growth.
The most extensively investigated hormone, adrenal glucocorticosteroid, accelerates late-gestation fetal lung maturation in low doses (250-252) and is widely used in premature infants to improve perinatal survival and lung function. However, high or repeated doses can inhibit postnatal somatic and lung growth (253). During the period of active postnatal alveolarization in rats, glucocorticoids inhibit secondary crest formation, accelerate alveolar wall thinning, decrease alveolar number and surface area (20, 254-257), diminish replication of fibroblasts, impair the conversion of types II to I pneumocytes (255, 258, 259), and alter collagen and elastin deposition (149, 254, 260, 261), resulting in a morphologic appearance resembling emphysema. In ferrets, corticosteroid treatment reduces size-corrected airway conductance, suggesting that the central airways are more sensitive to its effect than lung parenchyma (262). On the other hand, glucocorticoids can enhance other signals of lung growth. For example, both the rate and extent of postpneumonectomy alveolar growth are enhanced in adrenalectomized rats (88, 263-265); the enhancement is prevented by adrenocorticosteroid hormone replacement (263). Clinically, the wide-ranging effects of perinatal corticosteroid treatment may be long lasting (266, 267); therefore, balancing the short-term gain versus long-term adverse effects of glucocorticoid therapy in premature infants remains a difficult issue.
Growth factors. In pregnant rats, pneumonectomy increases DNA content in the fetal lung (268). Assuming that the maternal blood is not hypoxemic, data suggest that soluble growth factors released into maternal circulation are capable of crossing the placenta to stimulate fetal lung growth. However, initial findings of elevated serum growth hormone and insulin-like growth factor-1 levels in postpneumonectomy rats were later attributed to nonspecific surgical manipulation (269, 270). More likely, the postpneumonectomy response is mediated locally. In the fetal lamb, gene expression of insulin-like growth factor-I, a fibroblast mitogen, is reduced in lungs of experimental CDH and restored to normal by tracheal ligation (271). Postnatal insulin-like growth factor-I gene expression is also increased during accelerated lung growth after both liquid-based airway distension and pneumonectomy (271). A higher insulin-like growth factor-1 activity has been found in bronchoalveolar lavage fluid of postpneumonectomy rats (272); it is not clear whether the activity comes from parenchymal cells or the postoperative influx of circulatory neutrophils and macrophages.
Transgenic mice without epidermal growth factor receptor (EGFR -/-) show variably impaired alveolarization, branching morphogenesis, and type II pneumocyte differentiation (273, 274). Injection of EGF in rabbits accelerates lung maturation in utero (275) and induces widespread though transient epithelial mitogenic activities after birth (276). EGF and EGFR proteins are higher in 2-month-old growing dog lungs than in 1-year-old adult lungs, supporting a continuing regulatory role of the EGF axis during postnatal lung growth (277). In the swine after lobectomy, EGFR protein in the remaining lung is upregulated at 2 weeks, returning to baseline by 3 months (278). After lobar lung transplant, EGFR in the transplanted lobe is upregulated only after 3 months, coinciding with a slower increase in cell proliferation (105). Administration of EGF to rats augments postpneumonectomy lung growth and is associated with EGFR upregulation (279). Thus, the EGF axis could represent an avenue for modulating postnatal in addition to fetal lung growth (280). However, immature dogs studied 3 weeks after pneumonectomy do not show increased EGF or EGFR proteins above that in matched control animals despite active cell proliferation in the remaining lung (277), suggesting species-specific differences in the response to growth factors.
Keratinocyte growth factor. Keratinocyte growth factor (KGF) is a specific epithelial cell mitogen belonging to the FGF family (FGF7) and expressed in mesenchyme. Transgenic mice overexpressing KGF develop large cystic lungs resembling cystic adenomatoid malformation (281). Transgenic mice overexpressing a dominant-negative form of KGF receptor develop a trachea that branches only once (282). However, KGF (FGF7) -/- mice develop normal-looking lungs (283). Another ligand for the KGF receptor, FGF10 (KGF2), is also critical for lung development; FGF10 -/- mice have a trachea but no further branching (284).
In both adult and developing lungs, KGF induces alveolar type II pneumocyte proliferation in vitro and in vivo (285). KGF stimulates surfactant protein and phospholipid expression as well as transepithelial transport of fluid and electrolytes, minimizes injury and enhances repair of damaged epithelia, and may dampen the epithelial response to inflammatory mediators (286, 287). Exogenous KGF treatment is protective in injury models, including hyperoxia (288, 289), bleomycin (290, 291), radiation (291), and hydrochloric acid (292). Endogenous KGF mRNA is induced in neonatal rabbits exposed to hyperoxia (293), and KGF protein is increased in adult respiratory distress syndrome (294), suggesting a role in lung repair. In fetal sheep lung hypoplasia associated with CDH, KGF protein is reduced but increases after tracheal ligation concurrent with accelerated lung development (295). Overproduction of KGF in mice using a temporally inducible system (296) causes hyperplasia of type II pneumocytes and bronchial epithelial cells and increases inflammatory cells in the lung; effects disappear completely after cessation of KGF overproduction. Such conditional expression systems will be highly valuable for dissecting the effects of growth factors in models of lung growth.
Hepatocyte growth factor. Hepatocyte growth factor (HGF), derived from mesenchyme, is a heparin-binding growth factor implicated in organogenesis and compensatory growth of liver, kidney, and lung. HGF stimulates proliferation of airway and alveolar epithelial cell (297-299) and vascular endothelial cells (300) and enhances migration of type II pneumocytes (301). In fetal lung organ culture HGF, along with FGF family members, mediates branching morphogenesis (302). In postnatal lung, HGF facilitates lung repair after injury by minimizing collagen accumulation and fibrosis (303). Transpulmonary arterial transfer of human HGF gene into rat lung increases capillary density and blood flow (304). Serum HGF levels increase acutely in patients after pneumonectomy, although control data after thoracotomy alone are not available (305). In pneumonectomized mice, neutralization of endogenous HGF suppresses the compensatory increase of DNA synthesis in the remaining lung, whereas exogenous HGF administration stimulates DNA synthesis (306). Whether HGF-induced DNA synthesis translates into structural growth and functional augmentation remains to be seen.
TGF-[alpha]. TGF-[alpha], produced as a precursor proprotein and existing in membrane anchored as well as secreted forms, is mitogenic for epithelial and mesenchymal cells and also mediates remodeling in lung injury (307). TGF-[alpha] -/- mice have apparently normal lungs (308); however, mice overexpressing TGF-[alpha] show a marked increase in type II pneumocyte and fibroblast proliferation, with increased collagen deposition and fibrosis (309). Overexpression also causes severe pulmonary vascular disease, mediated through EGF receptor signaling in distal epithelial cells and associated with reduced VEGF expression in lung (310). TGF-[alpha] protein increases in bronchoalveolar lavage fluid after hyperoxic exposure and remains increased during the fibrotic period (311). Because TGF-[alpha] induces KGF mRNA in vitro in fibroblasts and KGF induces TGF-[alpha] in vitro in keratinocytes, there is likely to be important "cross-talk" between these growth factors in vivo as well.
Platelet-derived growth factor. Platelet-derived growth factor (PDGF), consisting of four gene products (PDGF-A-PDGF-D) that act via two receptor tyrosine kinases (PDGFR-[alpha] and PDGFR-[beta]), is strongly expressed in developing lung mesenchyme. In neonatal rats, PDGFR-[alpha] localizes to airway epithelium and PDGFR-[beta] to subendothelial perivascular areas and to airway and alveolar epithelium; their expression is delayed by postnatal hyperoxic exposure (312). PDGF-A participates in recruiting smooth muscle cells to alveolar sacs during alveolarization, but not specifically in early branching morphogenesis (313). PDGF-A(-/-) mouse lungs lack alveolar smooth muscle cells and exhibit reduced tropoelastin expression as well as elastin fiber deposition in lung parenchyma, associated with abnormal alveolar formation (157). It is possible that cells bearing PDGFR-[alpha] are progenitors of the tropoelastin-producing alveolar myofibroblasts, and the presence and distal spreading of these cells are necessary for the normal development of alveolar septum. PDGF has been implicated in postpneumonectomy compensatory lung growth in rats (314).
VEGF. VEGF is highly expressed in the airway and alveolar septum, placing it in a position to mediate airway-vascular interactions (315, 316). Heterozygous VEGF knockout mice die in embryonic life (317, 318), and postnatal inactivation of VEGF increases mortality (319). VEGF is induced by hypoxia and stretch and the expression modulated by other growth factors (315, 320-322). The major isoforms (VEGF-120, VEGF-164, and VEGF-188) act through two tyrosine kinase receptors localized mainly to endothelial cells: VEGFR-1 (Fit-1) and VEGFR-2 (FIk-1). VEGFR-1 is primarily responsible for endothelial cell maintenance and vascular organization (323), whereas VEGFR-2 regulates endothelial cell differentiation and migration, vascular permeability (324), and lung maturation (325). Members of the VEGF family, including placental growth factor, regulate angiogenesis in placenta, the fetal gas exchange organ (326). Early gestational mouse lungs express abundant VEGF-120 and VEGF-164; VEGF-188 becomes predominant as gestation progresses (327). Mice that produce only VEGF-120 survive with pruned pulmonary vasculature that grows poorly (327), suggesting that VEGF-120 is sufficient for pulmonary vascular development, but VEGF-164 and/or VEGF-188 are required for vascular growth and maintenance. Aberrant VEGF expression in transgenic mice disrupts both vascular and airway development (328). Although dexamethasone blocks in vitro VEGF induction, treatment in postnatal mice does not affect cell-specific expression of VEGF or the proportions of VEGF mRNA splice variants (329).
VEGF is an important factor for the growth of nonvascular alveolar cells (10, 330). Airway epithelial cells express VEGF and its receptors (331-333); VEGF stimulates alveolar epithelial cell proliferation as well as surfactant production in vitro (334). Chronic VEGF receptor blockade in adult rats results not only in pulmonary arterial pruning but also apoptosis of alveolar septal cells, resulting in emphysema-like morphology (330, 335). Expression of VEGF is regulated via transcriptional activation and mRNA stabilization of hypoxia-inducible factor-1[alpha] (HIF-1[alpha]) in hypoxia and via HIF-2[alpha] in normoxia (325, 336, 337). The administration of VEGF improves survival of premature mice with respiratory distress syndrome (325), suggesting a possible clinical application.
The capillary bed is essential for the growth and maintenance of alveolar septa, and the loss of capillaries leads to loss of septa. Not surprisingly, the relatively quiescent adult pulmonary vasculature contains large amounts of VEGF, serving as a reservoir for vascular repair, maintenance of capillary permeability, or as a survival factor for endothelial cells (316, 338). The reported effect of retinoic acid in rescuing failed alveolar septation in rats (159) must be associated with normal septal vascularization to be functionally useful. Retinoic acid presumably acts on the epithelium, but because epithelial cells are the major source of VEGF in the lung, it is possible that retinoic acid may also modulate VEGF (339) and other vascular growth factors to support alveolar capillary as well as epithelial growth.
Another vascular growth factor, angiopoietin, works in concert with VEGF and is regulated by hypoxia (340) but acts more on vascular organization, maturation, and maintenance than cell proliferation (6). High angiopoietin levels are found in the developing mouse lung (341, 342) and in lungs of patients with pulmonary hypertension (343).
TGF-[beta]. TGF-[beta] in its isoforms (TGF-[beta]1, TGF-[beta]2, and TGF-[beta]3) is highly expressed in lung (344), acting as a potent matrix inducer for wound repair and pulmonary vascular remodeling (345, 346) with complex effects on lung morphogenesis. Although TGF-[beta]1 may act as a paracrine inducer of VEGF in cultured fibroblasts and epithelial cells (347), in vivo overexpression of TGF-[beta]1 arrests fetal mouse lung development with thickened mesenchyme, abnormal vasculature, and decreased levels of VEGF (348). It is likely that the timing and mode of TGF-[beta] signaling as well as interactions with other growth factor pathways determine its effect on lung development and growth. Bone morphogcnetic protein receptor-2, a member of the TGF-[beta] receptor family, has been identified as the gene responsible for familial pulmonary hypertension (349, 350), attesting to the role of the TGF-[beta] family in maintaining normal lung vasculature. It is not clear whether vascular remodeling interferes with communication between pulmonary vasculature and the associated airways, possibly creating a physical barrier for delivery of growth factors from the airway.
Nitric oxide. Nitric oxide (NO) is synthesized from L-arginine via three NO synthase (NOS) isoenzymes: endothelial NOS (eNOS) and neuronal NOS are expressed in endothelial cells and neurons, respectively, and generate small amounts of NO on activation by Ca^sup 2+^, whereas inducible NOS (iNOS) is induced by various proinflammatory cytokines. NO mediates proliferation, migration, and differentiation of endothelial cells (351, 352) and interacts with multiple angiogenic growth factors. For example, the angiogenic action of VEGF requires NO production (351, 353). Gene deficiency of eNOS is associated with impaired fetal perfusion and growth restriction, impaired survival, limb reduction defects (354), and delayed wound healing (352). Mice deficient in eNOS exhibit elevated pulmonary vascular resistance in normoxia (355) as well as impaired alveolar and vascular formation when exposed to hypoxic stress during the period of alveolarization (356).
NO also mediates organ regeneration. Both flow and shear stress are determinants of endothelial NO release in vascular cells (357). In the liver after partial hepatectomy, increased blood flow and shear stress stimulate eNOS expression and elevated cytokine production triggers iNOS activity (358). Liver regeneration is impaired in iNOS gene knockout mice (359). In the remaining lung after pneumonectomy, the greater perfusion and shear stress increase intracellular Ca^sup 2+^ and calmodulin content (360), which increases eNOS expression independent of iNOS expression (361). Both eNOS- and iNOS-knockout mice show severely impaired postpneumonectomy lung growth; treatment of wildtype mice with the NOS inhibitor N^sup G^-nitro L-arginine methylester has the same effect (361), suggesting specific growth impairment caused by NO deficiency. Pneumonectomy in mice elevates serum levels of VEGF (361), which is known to interact variably with NO (353, 362). Although NOS gene knockout does not alter postpneumonectomy VEGF production, VEGF signaling may still be impaired at the receptor level. Mitogenic activity of VEGF requires activation of the mitogen-activated protein kinase cascade, a family of serine/threonine protein kinases involved in cell proliferation and migration known to be mediated by NO (362). Mitogen-activated protein kinase activation is also necessary for iNOS induction by interleukin-1 in endothelial cells (363). It remains possible that impaired postpneumonectomy lung growth in NO-deficient mice is at least partly mediated via blunting of VEGF signaling.
Retinoids. The retinoic acid-nuclear receptor complex regulates more than 300 target genes (364). Retinoids transcriptionally enhance in vitro synthesis of fibronectin, reduce the synthesis of collagenase and some keratins (365), and alter gene expression for surfactant-associated proteins (366). Retinoic acid regulates the expression of hox genes (367) during embryonic branching morphogenesis to favor growth of proximal airways and suppress distal epithelial buds (367, 368). Retinoic acid augments elastin gene expression in alveolar myofibroblasts (160, 161), alters the expression of receptors for various hormones and growth factors essential for maintaining a differentiated state of cultured alveolar epithelium (369), inhibits DNA biosynthesis, and enhances surfactant-phosphatidylcholine biosynthesis (370) consistent with accelerated epithelial maturation. Epithelial-mesenchymal actions of retinoic acid are partly mediated through induction of EGF receptors (371-373). EGF and retinoic acid synergistically increase collagen synthesis in fetal rat lung type II pneumocyte culture (374). Retinoic acid also exerts variable effects on VEGF production in vitro (339, 375).
The retinoic acid receptors subserve distinct functions. Retinoic acid receptor-[alpha] mediates alveolar growth after the perinatal period of alveolarization (376). Retinoic acid receptor-[beta] inhibits septation (377), whereas retinoic acid receptor-[gamma] is needed for normal lung elastin production and alveolarization (161). Administration of all-trans retinoic acid to normal neonatal rats and to older mice with a genetically failure of lung septation enhances alveolar septal formation without increasing specific alveolar surface area, suggesting that lengthening of septal crest is regulated by other mechanisms (159, 256, 378). In neonatal rats, retinoic acid prevents glucocorticoid-induced inhibition of alveolar septation (256). Retinoic acid also enhances epithelial repair, improves survival, and attenuates the inhibition of alveolar formation in neonatal rats after acute hyperoxic lung injury (254, 379, 380). Retinoic acid protects against the pathologic increase of alveolar volume and the reduction of alveolar number/surface area in adult emphysematous rats (381) and enhances compensatory lung growth in adult rats after pneumonectomy (382). However, retinoic acid does not alter airspace size or elastin or collagen gene expression in adult mice with emphysema (383). Retinoic acid-enhanced septal cell growth has not improved morphologic or physiologic indices of alveolar function in rats with elastase-induced emphysema (384) or in adult dogs after pneumonectomy (385, 386). Findings indicate additional complexities in structure-function integration of the growing lung that are yet to be understood.
Hypoxia. Exposure of fetal lung explants to severe hypoxia reversibly suppresses biochemical and morphologic markers of cell differentiation (387). However, because lung cells are normally exposed to a higher local O2 tension than cells of other organs and are capable of responding to a small decline in local O2 tension, in vitro studies conducted at O2 concentrations below approximately 5% may not mimic in vivo conditions at high altitude. In addition, the endothelium plays an essential role in the in vivo response to hypoxia. Cultured endothelial cells respond to small reductions of O2 tension by upregulating PDGF-B gene expression (388). An endothelial cell-derived soluble factor(s) is necessary for the increased polyamine uptake and metabolism observed in lungs exposed to hypoxia (389, 390). Polyamines (putrescine, spermidine, and spermine) are low molecular weight organic cations that interact with DNA and RNA to effect signal transduction, cell growth, and differentiation as well as survival after lung injury. Hypoxia also upregulates a unique set of stress proteins in endothelial cells in vitro, possibly mediating their longer survival and metabolic adaptation (391).
The identity of the cellular oxygen sensor is not known, but a favin-heme protein residing in the plasma membrane has been proposed (392). This heme protein functions as an nicotinamide adenine dinucleotide phosphate reduced oxidase, transferring electrons through favin and heme to oxygen and generating superoxide. In the presence of iron, superoxide is converted to reactive oxygen species, which induces rapid degradation of the inducible HIF-1[alpha] subunit. In hypoxia, a more stable HIF-1[alpha] subunit forms a heterodimer with constitutive HIF-1[alpha] subunit, thereby activating HIF-1 and leading to its nuclear translocation to enhance the transcription of various responsive genes. Activation of HIF-1 leads to induction of VEGF (329) and VEGF receptor-1 but not VEGF receptor-2 expression in endothelial cells in the lung (393). On the other hand, HIF-2[alpha] is implicated during normal lung development. Deficiency of HIF-2-[alpha] in neonatal mice is associated with low VEGF levels in alveolar cells, surfactant deficiency, arrested alveolar development, and fatal respiratory distress syndrome (325). Thus, signaling through HIF-VEGF axis emerges as a key mechanism for alveolar growth in hypoxia as well as in normoxia.
Role of Pluripotent Stem Cells
Hematologic stem cells develop endothelial cell phenotype when cultured in the presence of appropriate growth factors and form new blood vessels in vivo when injected subcutaneously with lung cancer cells (394). Engrafted hematologic stem cells facilitate neovascularization and functional recovery after focal cerebral ischemia (395). Murine embryonic stem cells cultured in the appropriate media can develop the phenotype of type II pneumocytes (396). Cultured bone marrow cells injected intravenously into mice after bleomycin lung injury engraft to lung parenchyma and develop the phenotype of type I but not type II pneumocytes (397). These transformations underscore the broad differentiation potential of stem cells and suggest that type I pneumocytes need not arise solely from transdifferentiation of type II pneumocytes. Systemic administration of stem cells has been plagued by a low engraftment rate and lack of a sustained response. Detailed characterization of resident progenitor cell subpopulations within the growing lung offers another approach to identify and isolate pluripotent cells capable of sustaining alveolar tissue growth (398).
After lung injury, a specialized pneumocyte subpopulation shows the capacity to proliferate (399, 400) and express telomerase, an enzyme complex that stabilizes the telomeres of chromosomes in actively dividing cells (401, 402). The telomerase complex includes a highly conserved catalytic subunit (telomerase reverse transcriptase) and an RNA oligonucleotide that primes the ends of newly replicated chromosomes for repair (401-403). Differentiating pneumocytes exhibit downregulated telomerase expression and activity. In normal adult tissues, telomere length and activity correlate with the potential of a cell to reinitiate proliferation on appropriate stimulation (404-406). In early lung development, pneumocytes evolve from a relatively undifferentiated precursor population that co-expresses surfactant proteins C and A, the Clara cell marker CC10, and neuroendocrine marker cGRP (407). As development progresses, these markers are expressed by separate differentiated lineages, with type II pneumocytes expressing only the surfactant proteins (408, 409). Type II pneumocytes can transdifferentiate into type I pneumocytes, serving as progenitors of the alveolar epithelial cell pool (409, 410). In the mouse, late gestation pneumocytes strongly express active telomerase reverse transcriptase; expression decreases after birth, and very low levels are sustained into adulthood (411), similar to observations in mature human lung (401, 402, 411, 412). In human epithelial lung cancer, telomerase reverse transcriptase is highly expressed (413). In adults, the ability of pneumocytes to divide is coupled with both survival and repopulation of damaged alveolar epithelial surface (414, 415). Telomerase activity is reinitiated in adult pneumocytes during the proliferative repair phase after hyperoxic injury (411), consistent with the presence of a subpopulation of pneumocyte progenitor cells capable of responding to injury.
At least four subpopulations of pneumocytes have been isolated from hyperoxic rat lung: nonproliferative/apoptotic, nonproliferative/nonapoptotic, proliferative/apoptotic, and proliferative/nonapoptotic, in order of decreasing abundance (414). The proliferative/nonapoptotic compartment might harbor potential progenitor cells, but it has not been possible to isolate those cells physically. An alternative approach is to use specific surface markers differentially expressed between quiescent and proliferating cells to sort out specific cell subtypes. For example, E-cadherin, a zonula adherens protein that allows cell-to-cell attachment, is critical for epithelial morphogenesis (416); loss of its expression is a marker for cell proliferation, migration, and tumorigenic transition (417-420). Higher levels of E-cadherin, [beta]-catenin, and [alpha]3 integrin are expressed in cells isolated from hyperoxic rats than from normoxic controls (421). Using these markers, type II pneumocytes have been fractionated into distinct subpopulations: the highly proliferative E-cadherin(-) subpopulation and the less proliferative E-cadherin(+) subpopulation (421).
The proliferative E-cadherin(-) pneumocyte subpopulation is further characterized by its high telomerase activity and damage resistance. In cultured pneumocytes isolated from hyperoxic animals, telomerase activity of the E-cadherin(-) subpopulation is threefold higher than in normoxic control cells (411), whereas telomerase activity of the hyperoxic E-cadherin(+) subpopulation is similar to that of normoxic control cells. Compared with the original pneumocyte population from hyperoxic animals, the E-cadherin(-) subpopulation show markedly less apoptosis, whereas the E-cadherin(+) subpopulation shows more apoptosis (421). The E-cadherin(-) pneumocyte subpopulation may represent a proliferating, nonapoptotic, and telomerase(+) compartment that can effectively resist or repair hyperoxic damage. This approach of using differential surface markers holds considerable promise for identifying progenitor cell subpopulations as targets for further manipulation.
FUNCTIONAL CORRELATES AND LIMITS OF INDUCED LUNG GROWTH
Compensatory Versus Reparative Lung Growth
Compensatory lung growth differs from reparative growth after lung injury in gene expression, biochemistry, morphology, and organ function. Postpneumonectomy induction of tropoelastin and type I procollagen mRNA expression localizes to alveolar walls and alveolar ducts in a pattern similar to that during postnatal development (91). Elastin and collagen content of the lung increases proportionally with the increase in dry lung weight (422, 423), and connective tissue morphology is largely preserved. In acute lung injury and fibrosis, there is initial collagen breakdown (424) followed by disproportionately (70- to 80-fold) increased lung elastin mRNA, localized preferentially to the muscularis of conducting airways and interstitial cells in fibrotic foci associated with distorted elastic fiber morphology (425). Hypertrophy of type II pneumocytes isolated from the remaining lung postpneumonectomy (426) is in the most active phase of the cell cycle but, in contrast to the response in acute lung injury, is not activated for surfactant lipid biosynthesis or storage (427). Although the remaining lung after pneumonectomy is not "inflamed" as in injury models, there is an initial influx of circulatory proteins and cells associated and an expanded extravascular albumin space (272). This influx is likely a vital process to provide growth factors for mitogenic activities. Pulmonary endothelial permeability is acutely elevated after major lung resection (428) and may precipitate pulmonary edema in patients with inadequate pulmonary vascular reserves. However, experimental pneumonectomy does not increase extravascular lung water formation at a given level of hemodynamic challenge (429). This is likely due to the high compliance and capacitance of the pulmonary vascular bed, as lung mass must be reduced by more than 60% before pulmonary vascular resistance and capillary pressure is increased in the isolated lung perfused at a constant flow (430). Neither vascular congestion nor extravasated protein and water contribute to the progressive weight gain in lungs following pneumonectomy (431).
Nonstructural Sources of Adaptation: Recruitment of Reserves
In any physiologic transport system, the capacity of the system exceeds normal loading by a factor of 2 to 7 (432), reflecting the existence of large physiologic reserves (or safety factor), which are essential for safeguarding against unexpected perturbation. Maintenance of physiologic reserves is a primary goal of adaptive regulation and a crucial factor in determining (1) the threshold for reinitiation of structural response and (2) the magnitude of functional compensation. Alveolar-capillary reserves for diffusive oxygen transport is reflected by the recruitment of DL, which increase more than 100% from rest to exercise in a linear relationship with respect to pulmonary blood flow (433, 434) (Figure 5); DL also increases approximately 25% with alveolar volume (435). At rest, only approximately 50% of alveoli and capillaries are sufficiently patent to participate in gas exchange, and capillary erythrocytes are nonuniformly distributed because partially collapsed capillaries particularly at lung apices allow plasma but not erythrocyte flow (436). On exercise, the number of perfused capillaries increases directly with perfusion pressure (437), and the number of distended alveoli increases with tidal volume, leading to (1) greater effective alveolar-capillary surface area, which increases DL, and (2) greater traction on small airways, which increases airway diameter, reduces flow resistance, and facilitates uniform distribution of ventilation. Increased flow and pressure also allows more uniform regional erythrocyte flows, resulting in better matching of diffusion to perfusion that theoretically can account for 30-50% of the augmentation in DL from rest to peak exercise (438).
Lung volume, alveolar-capillary surface area, barrier thickness for diffusion, and pulmonary capillary blood volume are major anatomical determinants of DL. Estimates of DL from these structural parameters in fixed lungs agree well with that measured physiologically at heavy exercise in the same animal (439). Thus, alveolar structure determines the upper limit of diffusive oxygen transport; this limit is normally not approached except at peak exercise when physiologic reserves are more fully used. In the event of loss of alveoli, ventilation and blood flow are diverted to the remaining units, causing alveolar-capillary distension and recruitment of reserves in those units. As a result, apparent DL at a given workload is higher than that expected from the severity of anatomic destruction. Alveolar-capillary recruitment is a vital and ubiquitous mechanism of functional compensation. Because of recruitment, oxygen transport is relatively preserved until more than 50% of the alveolar-capillary surface is obliterated (440). For example, resection of 45% of lung in dogs results in no appreciable impairment of aerobic capacity and only 25% reduction of DL at a given workload (97, 441). It is possible to separate the functional consequences of new alveolar tissue growth from the concurrent recruitment of physiologic reserves in the remaining alveoli (Figure 5). Based on experimental data from animals and clinical data from patients with various cardiopulmonary diseases, the slope of the DL versus pulmonary blood flow relationship can provide an index of the functional integrity or "recruitability" of existing alveolar-capillary network. On the other hand, induced growth of new gas exchange tissue is evidenced by an increased DL at any given cardiac output and an elevated intercept of the entire relationship (442).
Limits Imposed by Dysanaptic Lung Growth
Normal lung growth involves balanced expansions of all intra-acinar tissue components, conducting structures, as well as the bony and muscular thorax leading to proportional enhancement in gas exchange, mechanics, and hemodynamic function (Figure 6). Dysanaptic (i.e., unequal) lung growth refers to the observation that conducting airways and blood vessels, which primarily form in fetal life, demonstrate limited growth potential compared with acinar tissue during postnatal development (443-445) or during compensatory lung growth induced by high-altitude residence (111) or pneumonectomy (446, 447). The term was originally invoked to explain the large variation in maximal expiratory flow rate relative to lung volume among normal subjects (445); it was later used (111) to explain the small airway dimensions and low maximal flow rate with respect to lung volume observed in high altitude natives. Hypoxia-enhanced alveolar growth without corresponding enhancement in the growth of conducting structures creates an apparent airway limitation that diminishes the overall functional benefit of alveolar growth (Figure 7). The opposing effects of high-altitude exposure on lung and thoracic growth are other manifestations of dysanaptic growth where retardation of rib cage growth may effectively set the limit of functional compensation that can be achieved through stimulation of alveolar tissue growth alone.
Airway-parenchyma dissociation also occurs during postpneumonectomy lung growth, evidenced by a disproportionally low maximal expiratory flow rate, increased airways resistance, and elevated work of breathing in both animal models (184, 447-450) as well as in patients after lung resection (451-454). Abnormal airway function persists in spite of a doubling of lung volume and normalization of the static recoil of the remaining lung parenchyma. Anatomic studies show that volume and cross-sectional area of conducting airways in the remaining lung increase less than expected from the volume increase in lung parenchyma (93, 446, 455). Early after pneumonectomy, conducting airways elongate with little change in diameter, which markedly elevates airflow resistance and work of breathing because more than 50% of total airway cross-sectional area has been removed. Subsequently, airways slowly dilate, resulting in partial mitigation of airflow resistance and work of breathing (184, 456). In contrast to conducting airways, respiratory bronchioles proliferate (457) in proportion to the increase in alveolar air and tissue volume; that is, all intra-acinar structures grow equally. An increased number and volume of respiratory bronchioles might be expected to increase total airway cross-sectional area and improve diffusive gas mixing, but the anticipated benefit is offset by a longer total acinar airway length for gas diffusion.
Postpneumonectomy alveolar growth also does not normalize long-term pulmonary vascular resistance (184), suggesting a similar lag between structural adaptation of pulmonary blood vessels and that of the parenchyma. Limited compensation in airflow and vascular conductances regardless of somatic maturity or extent of septal tissue growth underscores the relative lack of plasticity in conducting structures. Because these structures cannot adapt by adding more branches, they effectively impose an upper limit of functional compensation achievable by septal tissue regrowth, as more lung units are lost.
Dysanaptic growth could potentially impose a functional limit after therapeutic intervention such as pediatric lobar lung transplant. In spite of normal alveolar growth, conducting airways in the transplanted lobe may not remodel sufficiently during subsequent somatic growth to maintain normal airflow conductance in the graft. Dysanaptic lung growth could also occur as a long-term sequelae of BPD or chronic lung disease of prematurity where small airway obstruction persists despite normalization of lung volume and mechanical function (458, 459). Yet another type of dysanaptic growth can result from nonuniform stimulation of alveolar septal cells. For example, selective stimulation of epithelial cell proliferation via exogenous growth factors could potentially outstrip capillary blood supply, resulting in more alveolar tissue but limited improvement in gas exchange. Tracheal occlusion accelerates lung organogenesis in fetal lambs with CDH, leading to increased mesenchyme tissue but disproportionately fewer type II cells, a surfactant deficit (460), and altered alveolar morphology incompatible with efficient gas exchange (461) consistent with the lack of clinical benefit (462). Exogenous retinoic acid given to adult dogs after right pneumonectomy selectively enhances alveolar capillary endothelial cell growth in the remaining lung without stimulating other alveolar cell compartments, leading to distortion of alveolar architecture and a lack of overall functional benefit (385, 386). Such distortions cannot be predicted from molecular or cellular studies alone. Further investigation should clarify the extent and significance of such mismatches.
Limits Imposed by Heart-Lung-Thorax Interaction
Compensatory lung growth is thought to occur in children after pneumonectomy, inferred indirectly from long-term improvement in their pulmonary function (454, 463-465). However, more pronounced and persistent functional abnormalities in adult patients after pneumonectomy (466-469) suggest that compensatory lung growth in adults is likely minimal; instead, recruitment of existing physiologic reserves is the main source of functional compensation. Comparative responses between animals and patients have identified the abnormal mechanical interactions among heart, lung, and the thorax as the major factors limiting adaptation in adult patients. Unlike in animals, postpneumonectomy patients who have relatively normal remaining lungs and have not received any adjuvant therapy show limited expansion and reduced compliance of the remaining lung compared with age-matched control subjects (98, 452). Gas exchange impairment is generally mild until more than 67% of lung tissue is removed (468, 470). Long-term aerobic capacity is markedly limited because of concurrent cardiac and respiratory muscle dysfunction. Maximal stroke volume, ventilatory capacity, and respiratory muscle power are reduced more than 50% (452, 470, 471). Peak pulmonary arterial pressure during exercise is no higher than that expected in a normal subject (468, 472), suggesting impaired right ventricular response to an elevated afterload, that is, an inability to use the Starling mechanism of diastolic ventricular dilation to preserve stroke volume. Airflow resistance is increased, whereas effective respiratory muscle mass is reduced. Abnormalities cannot be attributed to respiratory muscle or cardiovascular deconditioning (470) but are compatible with consequences of anatomic restriction of the heart, rib cage, and diaphragm caused by pleuromediastinal serofibrous adhesions, which are present in patients but absent in pneumonectomized dogs. Fibrous adhesions distort and immobilize the thorax and diaphragm, reduce compliance of the cardiac fossa, irreversibly limit lung expansion, and attenuate strain-related signals for lung growth.
Reasons for persistent serofibrous accumulation in patients are not clear but are likely related to a large residual hemothorax, postoperative inactivity, poor pleural lymphatic clearance, and/or an intense pleuromediastinal inflammatory response. It remains possible that compensatory lung growth might be induced in adult patients as in quadrupeds if pleuromediastinal reactions could be minimized by strategies such as separating the pleural surfaces with an inert gas (473), instillation of a lubricant solution (474), or the use of antiadhesion barriers (475). Long-term lung function tends to be best in the most physically active patients; hence, aggressive postoperative rehabilitation and sustained exercise programs may help maintain the mobility of the diaphragm and mediastinum (476). These issues of mechanical interdependence among intrathoracic structures cannot be predicted from animal studies alone; they are broadly relevant to the adaptive response not only after pneumonectomy but also in other destructive lung diseases.
Growth Induction and Carcinogenesis
A newly recognized characteristic of induced lung growth is the potential for the growth-enhancing microenvironment to stimulate tumor cell proliferation. In mice exposed to a carcinogen, pneumonectomy acts as a tumor promoter and increases pulmonary adenoma multiplicity as much as sevenfold. The effect is observed whether pneumonectomy is performed before or after administration of carcinogen (84). In addition, pneumonectomy promotes metastasis of systemic tumor to the lung. In pneumonectomized mice injected with melanoma cells, there is up to threefold more pulmonary melanoma cell metastases than in sham control subjects (477). The greatest numbers of tumors are present when melanoma cells are injected during the initial rapid phase of compensatory lung growth. In contrast, pneumonectomy does not enhance subcutaneous growth of melanoma tumors, reflecting the selective local nature of metastatic enhancement. Observations support the premise that after pneumonectomy, the microenvironment of the remaining lung regulates the initiation, promotion, and progression of metastatic cancer. This response may involve VEGF; elevated serum VEGF levels in patients after surgical lung resection for cancer have been linked to the subsequent development of aggressive secondary lung metastases perhaps via an increased capillary permeability (478). These observations provide a framework for future studies to define conditions within the lung that differentially promote normal and abnormal cellular growth.
Current understanding of growth induction in postnatal lung highlights several key issues and caveats in need of further research:
1. At the molecular level, gene knockout models have been invaluable in elucidating the function of specific proteins during development, but interpretation is limited by the possibility of compensatory or redundant mechanisms. It remains uncertain whether the same gene products are implicated during development as during reinduction of growth in the mature lung and whether their molecular interactions are similar (479). The developing lung differs from the adult/nongrowing lung in mechanical stresses, hormonal/growth factor levels, responsiveness to a given signal and epithelial-mesenchymal-endothelial interactions. Although it is convenient to assume that morphogenetic signaling pathways controlling lung development become reactivated during reinduction of growth in the mature lung, interpretation of earlier studies, reviewed by Cagle and Thurlbeck (464), cautions against this assumption and is supported by recent comparisons showing divergent patterns of surfactant protein expression and EGF axis activation in dogs during normal and compensatory lung growth (277). More comparative studies are needed to define the similarities and differences between different types of lung growth.
2. At the cellular level, cell architecture and mechanical stress distribution are tightly coupled to metabolic processes, including cell growth, proliferation, differentiation, and turnover. The properties, organization, and distribution of stress-bearing cytoskeletal filaments and fibers critically determine the pattern of mechanotransduction. The central role of elastin in secondary crest formation requires further delineation. New culture systems that more precisely mimic the movements and stresses of developing elastic tissues and the use of "nanotechnology" may offer new insight into the cellular assembly that confers macroscopic mechanical properties of stress-bearing fibers. There is a need to develop specific models of mechanical loading on alveolar capillaries to study the mechanisms of capillary growth and remodeling in the lung. Another promising direction, arising from the rapidly evolving advances in stem cell biology, is to isolate and characterize progenitor cell subpopulations within the lung, and testing whether implantation of exogenous stem cells or stimulation of endogenous stem cells can induce or accelerate alveolar cellular growth.
3. At the organ level, the structural basis of how new alveolar tissue is added postnatally remains incompletely understood. Current understanding of the feedback communication among growing structures, for example, between bronchial and alveolar epithelium or among alveolar epithelium, interstitium, and endothelium, is sketchy without a coherent integration of how the extensive array of hormones and paracrine growth factors known to act on various alveolar compartments are coordinated to bring about balanced three-dimensional structural growth. Secondary alveolar crest formation only partially account for the observed septal growth. Additional mechanisms for increasing alveolar complexity related to other anatomical compartments of the acinus, such as respiratory bronchioles and alveolar ducts, need to be delineated. Questions remain regarding how overall alveolar-capillary architecture is governed and how septal growth is ultimately limited.
4. At the translational level, mechanical strain and chronic hypoxia emerge as major signals for reinduction of alveolar growth in a threshold-dependent manner, whereas metabolic and hormonal mediators quantitatively and qualitatively modulate the response. Although this knowledge offers exciting possibilities for designing pharmacologic or physiologic manipulations to induce lung growth, it should be recognized that selective stimulation of one or a few alveolar cell populations is likely to be of limited utility. To achieve optimal function, epithelial growth must be matched to that of the matrix, capillary network, conducting blood vessels, and airways as well as the bony thorax. Dysanaptic responses among structural components, distortion of alveolar architecture, or mismatch among intrathoracic organs limit the effectiveness of induced alveolar tissue growth. Herein lies a caveat of the "magic pill" approach to growth induction because no single agent can possibly replicate the coordination seen in normal lung growth. Multiple and possibly all of the regulatory pathways must be activated synchronously to orchestrate a balanced and functionally useful enhancement of lung growth.
Several lines of basic research have approached clinical application, such as exogenous retinoic acid for patients with emphysema (480) and perfluorocarbon lung distention for neonates with CDH (481-483). Other applications yet to be explored include inducing compensatory lung growth in children who survive BPD beyond the injury-repair stage or those who survive repair of CDH but are left with small lungs and marginal gas exchange capacity. For example, nasal continuous positive airway pressure has been reported to mitigate the development and severity of BPD in preterm infants (484, 485). Chronic intermittent continuous positive airway pressure in survivors of BPD or CDH might provide sufficient mechanical signals to augment subsequent lung growth. Potential applications should be based on appropriate animal models that mimic the inciting injury, the organ response, as well as the long-term growth pattern seen in humans. The baboon model of mild-to-moderate BPD (486) and the neonatal lamb model of CDH (487) could be very valuable for testing these strategies. The pneumonectomy model is particularly robust because the remaining lung is not "injured" in the classic sense, and the anatomic loss of alveoli and lung function is quantifiable and reproducible. As the bulk of research thus far involves rodents, there is a need to define rigorously the structural basis and functional consequences of interspecies differences within and among models of compensatory lung growth.
Finally, reinitiating lung growth may increase susceptibility to carcinogenesis and metastasis. Implication of this tantalizing observation remains to be seen, but it is an important reminder that there are no free rides.
1. Thurlbeck WM. Lung growth and development. In: Thurlbeck WM, Churg AM, editors. Pathology of the lung. New York: Thieme Medical; 1995. p. 37-87.
2. Dunnill MS. Postnatal growth of the lung. Thorax 1962;17:329-333.
3. Merkus PJ, ten Have-Opbroek AA, Quanjer PH. Human lung growth: a review. Pediatr Pulmonol 1996;21:383-397.
4. Burri PH. Structural aspects of prenatal and postnatal development and growth of the lung. In: McDonald JA, editor. Lung growth and development. New York: Marcel Dekker; 1997. p. 1-35.
5. Meyrick B, Reid LM. Ultrastructure of alveolar lining and its development. In: Hudson WA, editor. Development of the lung. New York: Marcel Dekker; 1977. p. 135-214.
6. Nguyen LL, D'Amore PA. Cellular interactions in vascular growth and differentiation. Int Rev Cytol 2001;204:1-48.
7. Risau W. Mechanisms of angiogenesis. Nature 1997;386:671-674.
8. deMello DE, Sawyer D, Galvin N, Reid LM. Early fetal development of lung vasculature. Am J Respir Cell Mol Biol 1997;16:568-581.
9. Kurz h, Burri PH, Djonov VG. Angiogenesis and vascular remodeling by intussusception: from form to function. News Physiol Sci 2003; 18:65-70.
10. Jakkula M, Le Cras TD, Gebb S, Hirth KP, Tuder RM, Voelkel NF, Abman SH. Inhibition of angiogenesis decreases alveolarizalion in the developing rat lung. Am J Physiol Lung Cell Mol Physiol 2000; 279:L600-L607.
11. Charan NB, Carvalho P. Angiogenesis in bronchial circulatory system after unilateral pulmonary artery obstruction. J Appl Physiol 1997; 82:284-291.
12. Mitzner W, Lee W, Georgakopoulos D, Wagner E. Angiogenesis in the mouse lung. Am J Pathol 2000;157:93-101.
13. Bukhalovskii IN, Popov YA. Detection and clinical significance of functional intrapulmonary vascular anastomoses in patients with chronic nonspecific lung diseases. Cor Vasa 1979;21:398-406.
14. Schraufnagel DE. Monocrotaline-induced angiogenesis: differences in the bronchial and pulmonary vasculature. Am J Pathol 1990;137: 1083-1090.
15. Hopkins N, Cadogan E, Giles S, McLoughlin P. Chronic airway infection leads to angiogenesis in the pulmonary circulation. J Appl Physiol 2001;91:919-928.
16. Schraufnagel DE, Sekosan M, McGee T, Thakkar MB. Human alveolar capillaries undergo angiogenesis in pulmonary veno-occlusive disease. Eur Respir J 1996;9:346-350.
17. Mortola JP, Saetta M, Bartlett D Jr. Postnatal development of the lung following denervation. Respir Physiol 1987;67:137-145.
18. Dotta A, Mortola JP. Postnatal development of the denervated lung in normoxia, hypoxia, or hyperoxia. J Appl Physiol 1992;73:1461-1466.
19. Hislop AA, Odom NJ, McGregor CG, Haworth SG. Growth potential of the immature transplanted lung: an experimental study. J Thorac Cardiovasc Surg 1990;100:360-370.
20. Blanco LN, Frank L. The formation of alveoli in rat lung during the third and fourth postnatal weeks: effect of hyperoxia, dexamethasone, and deferoxamine. Pediatr Res 1993;34:334-340.
21. Massaro D, Massaro GD. Regulalion of the architectural development of the lung. In: Crystal RG, Barnes PJ, West JB, Weibel ER, editors. The lung: scientific foundations. Philadelphia: Lippincott-Raven; 1997. p. 1027-1034.
22. Cooney TP, Thurlbeck WM. Pulmonary hypoplasia in Down's syndrome. N Engl J Med 1982;307:1170-1173.
23. Schloo BL, Vawter GF, Reid LM. Down syndrome: patterns of disturbed lung growth. Hum Pathol 1991;22:919-923.
24. Thurlbeck WM, Cooney TP. Dysmorphic lungs in a case of leprechaunism: case report and review of literature. Pediatr Pulmonol 1988; 5:100-106.
25. Richards DS. Complications of prolonged PROM and oligohydramnios. Clin Obstet Gynecol 1998;41:817-826.
26. Beals DA, Schloo BL, Vacanti JP, Reid LM, Wilson JM. Pulmonary growth and remodeling in infants with high-risk congenital diaphragmatic hernia. J Pediatr Surg 1992; 27:997-1001; discussion 1001-1002.
27. Smith NP, Jesudason EC, Losty PD. Congenital diaphragmatic hernia. Paediatr Respir Rev 2002;3:339-348.
28. Flake AW, Crombleholme TM, Johnson MP, Howell LJ, Adzick NS. Treatment of severe congenital diaphragmatic hernia by fetal tracheal occlusion: clinical experience with fifteen cases. Am J Obstet Gynecol 2000;183:1059-1066.
29. Marven SS, Smith CM, Claxton D, Chapman J, Davies HA, Primhak RA, Powell CV. Pulmonary function, exercise performance, and growth in survivors of congenital diaphragmatic hernia. Arch Dis Child 1998;78:137-142.
30. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease: bronchopulmonary dysplasia. N Engl J Med 1967;276:357-368.
31. Northway WH Jr, Moss RB, Carlisle KB, Parker BR, Popp RL, Pitlick PT, Eichler I, Lamm RL, Brown BW Jr. Late pulmonary sequelae of bronchopulmonary dysplasia. N Engl J Med 1990;323:1793-1799.
32. Kurzner SI, Garg M, Bautista DB, Sargent CW, Bowman CM, Keens TG. Growth failure in bronchopulmonary dysplasia: elevated metabolic rates and pulmonary mechanics. J Pediatr 1988;112:73-80.
33. Bhatt AJ, Pryhuber GS, Huyck H, Watkins RH, Metlay LA, Maniscalco WM. Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 164:1971-1980.
34. Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003;8:73-81.
35. Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res 1999; 46:641-643.
36. Husain AN, Siddiqui NH, Stocker JT. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol 1998;29:710-717.
37. Bartlett D Jr, Areson JG. Quantitative lung morphology in newborn mammals. Respir Physiol 1977;29:193-200.
38. Mercer RR, Russell ML, Crapo JD. Alveolar septal structure in different species. J Appl Physiol 1994;77:1060-1066.
39. Burri PH. The postnatal growth of the rat lung: III: morphology. Anat Rec 1974;180:77-98.
40. Dawson AB. Additional evidence of the failure of epiphyseal union in the skeleton of the rat: studies on wild and captive Norway rats. Anat Rec 1934;60:501-5I1.
41. Thurlbeck WM. Lung growth and alveolar multiplication. Pathobiol Annu 1975;5:1-34.
42. Lechner AJ, Banchero N. Advanced pulmonary development in newborn guinea pigs (Cavia porcellus). Am J Anat 1982;163:235-246.
43. Ross KA, Thurlbeck WM. Lung growth in newborn guinea pigs: effects of endurance exercise. Respir Physiol 1992;89:353-364.
44. Forrest JB, Weibel ER. Morphometric estimation of pulmonary diffusion capacity: VII: the normal Guinea pig lung. Respir Physiol 1975; 24:191-202.
45. Tucker A, McMurtry IF, Reeves JT, Alexander AF, Will DH, Grover RF. Lung vascular smooth muscle as a determinant of pulmonary hypertension at high altitude. Am J Physiol 1975;228:762-767.
46. Zuck TT. Age order of epiphyseal union in the guinea pig. Anat Rec 1938;70:389-399.
47. Kovar J, Sly PD, Willet KE. Postnatal alveolar development of the rabbit. J Appl Physiol 2002;93:629-635.
48. Mathieu-Costello O, Willford DC, Fu Z, Garden RM, West JB. Pulmonary capillaries are more resistant to stress failure in dogs than in rabbits. J Appl Physiol 1995;79:908-917.
49. Birks EK, Mathieu-Costello O, Fu Z, Tyler WS, West JB. Comparative aspects of the strength of pulmonary capillaries in rabbit, dog, and horse. Respir Physiol 1994;97:235-246.
50. Fu Z, Heldt GP, West JB. Increased fragility of pulmonary capillaries in newborn rabbit. Am J Physiol Lung Cell Mol Physiol 2003;284: L703 -L709.
51. Mauderly JL. Effect of age on pulmonary structure and function of immature and adult animals and man. Fed Proc 1979;38:173-177.
52. Davies P, Reid L., Lister G, Pitt B. Postnatal growth of the sheep lung: a morphometric study. Anat Rec 1988;220:281-286.
53. Winkler GC, Cheville NF. Morphometry of postnatal development in the porcine lung. Anal Rec 1985;211:427-433.
54. Winkler GC, Cheville NF. The neonatal porcine lung: ultrastructural morphology and postnatal development of the terminal airways and alveolar region. Anat Rec 1984;210:303-313.
55. Mansell AL, Collins MH, Johnson E Jr, Gil J. Postnatal growth of lung parenchyma in the piglet: morphometry correlated with mechanics. Anat Rec 1995;241:99-104.
56. Hislop A, Howard S, Fairweather DV. Morphometric studies on the structural development of the lung in Macaca fascicularis during fetal and postnatal life. J Anat 1984;138:95-112.
57. Swindler DR, Wood CD. Thorax, part 5. In: An atlas of primate gross anatomy. Seattle, WA: University of Washington Press; 1973. p. 184-201.
58. Weibel ER. Lung morphometry and models in respiratory physiology. In: Chang HK, Paiva M, editors. Respiratory physiology, an analytical approach. New York: Marcel Dekker; 1989. p. 1-56.
59. Mostyn EM, Helle S, Gee JBL, Bentivoglio LG, Bates DV. Pulmonary diffusing capacity of athletes. J Appl Physiol 1963;18:687-695.
60. Hoppeler H, Altpeter E, Wagner M, Turner DL, Hokanson J, König M, Stalder-Navarro VP, Weibel ER. Cold acclimation and endurance training in guinea pigs: changes in lung, muscle and brown fat tissue. Respir Physiol 1995;101:189-198.
61. Bartlett D Jr. Postnatal growth of the mammalian lung: influence of exercise and thyroid activity. Respir Physiol 1970;9:50-57.
62. Gehr P, Hugonnaud C, Burri PH, Bachofen H, Weibel ER. Adaptation of the growing lung to increased VO^sub 2^: III: the effect of exposure to cold environment in rats. Respir Physiol 1978;32:345-353.
63. Geelhaar A, Weibel ER. Morphometric estimation of pulmonary diffusion capacity: 3: the effect of increased oxygen consumption in Japanese Waltzing mice. Respir Physiol 1971;11:354-366.
64. Gail DB, Massaro GD, Massaro D. Intraspecies differences in lung metabolism and granular pneumocyte mitochondria. Respir Physiol 1975;23:175-180.
65. Massaro D, Teich N, Massaro GD. Postnatal development of pulmonary alveoli: modulation in rats by thyroid hormones. Am J Physiol 1986; 250:R51-R55.
66. Liu M, Skinner SJ, Xu J, Han RN, Tanswell AK, Post M. Stimulation of fetal rat lung cell proliferation in vitro by mechanical stretch. Am J Physiol 1992;263:L376-L383.
67. Harding R, Hooper SB. Regulation of lung expansion and lung growth before birth. J Appl Physiol 1996;81:209-224.
68. Thibeault DW, Haney B. Lung volume, pulmonary vasculature, and factors affecting survival in congenital diaphragmatic hernia. Pediatrics 1998;101:289-295.
69. Gilbert KA, Rannels DE. Increased lung inflation induces gene expression after pneumonectomy. Am J Physiol 1998;275:L21-L29.
70. Berg JT, Fu Z, Breen EC, Tran HC, Mathieu-Costello O, West JB. High lung inflation increases mRNA levels of ECM components and growth factors in lung parenchyma. J Appl Physiol 1997;83:120-128.
71. Zhang S, Garbutt V, McBride JT. Strain-induced growth of the immature lung. J Appl Physiol 1996;81:1471-1476.
72. Nobuhara KK, Fauza DO, DiFiore JW, Hines MH, Fackler JC, Slavin R, Hirschl R, Wilson JM. Continuous intrapulmonary distension with perfluorocarbon accelerates neonatal (but not adult) lung growth. J Pediatr Surg 1998;33:292-298.
73. Rannels DE. Role of physical forces in compensatory growth of the lung. Am J Physiol 1989;257:L179-L189.
74. Cohn R. Factors affecting the postnatal growth of the lung. Anat Rec 1939;75:195-205.
75. Hassler F. Ueber compensatorische hypertrophie der lunge. Virchows Arch Pathol Anat Physiol 1892;128:527-536.
76. Rannels DE, Rannels SR. Compensatory growth. In: Crystal RG, West JB, Barnes PJ, Weibel ER, editors. The lung: scientific foundations, 2nd ed. Philadelphia: Lippincott-Raven; 1997. p. 1035-1046.
77. Langsten C, Sachdeva P, Cowan MJ, Haines J, Crystal RG, Thurlbeck WM. Alveolar multiplication in the contralateral lung after unilateral pneumonectomy in the rabbit. Am Rev Respir Dis 1977;115:7-13.
78. Buhain WJ, Brody JS. Compensatory growth of the lung following pneumonectomy. J Appl Physiol 1973;35:898-902.
79. Bardocz S, Tatar-Kiss S, Kertai P. The effect of alpha-difluoromethyl-ornithine on ornithine decarboxylase activity in compensatory growth of mouse lung. Acta Biochim Biophys Hung 1986;21:59-65.
80. Thurlbeck WM, Galaugher W, Mathers J. Adaptive response to pneumonectomy in puppies. Thorax 1981;36:424-427.
81. McBride JT. Lung volumes after an increase in lung distension in pneumonectomized ferrets. J Appl Physiol 1989;67:1418-1421.
82. Rannels DE, Burkhart LR, Watkins CA. Effect of age on the accumulation of lung protein following unilateral pneumonectomy in rats. Growth 1984;48:297-308.
83. Landesberg LJ, Ramalingam R, Lee K, Rosengart TK, Crystal RG. Upregulation of transcription factors in lung in the early phase of postpneumonectomy lung growth. Am J Physiol Lung Cell Mol Physiol 2001;281:L1138-L1149.
84. Brown LM, Malkinson AM, Rannels DE, Rannels SR. Compensatory lung growth after partial pneumonectomy enhances lung tumorigenesis induced by 3-methylcholanthrene. Cancer Res 1999;59:5089-5092.
85. Brown LM, Rannels SR, Rannels DE. Implications of post-pneumonectomy compensatory lung growth in pulmonary physiology and disease. Respir Res 2001;2:340 -347.
86. Cagle PT, Langsten C, Goodman JC, Thurlbeck WM. Autoradiographic assessment of the sequence of cellular proliferation in postpneumonectomy lung growth. Am J Respir Cell Mol Biol 1990;3:153-158.
87. Brody JS, Burki R, Kaplan N. Deoxyribonucleic acid synthesis in lung cells during compensatory lung growth after pneumonectomy. Am Rev Respir Dis 1978;117:307-316.
88. Rannels DE, Stockstill B, Mercer RR, Crapo JD. Cellular changes in the lungs of adrenalectomized rats following left pneumonectomy. Am J Respir Cell Mol Biol 1991;5:351-362.
89. Thet LA, Law DJ. Changes in cell number and lung morphology during early postpneumonectomy lung growth. J Appl Physiol 1984;56:975-978.
90. Cowan MJ, Crystal RG. Lung growth after unilateral pneumonectomy: quantitation of collagen synthesis and content. Am Rev Respir Dis 1975;111:267-277.
91. Koh DW, Roby JD, Starcher B, Senior RM, Pierce RA. Postpneumonectomy lung growth: a model of reinitiation of tropoelastin and type I collagen production in a normal pattern in adult rat lung. Am J Respir Cell Mol Biol 1996;15:611-623.
92. Gilbert KA, Rannels DE. From limbs to lungs: a newt perspective on compensatory lung growth. News Physiol Sci 1999;14:260-267.
93. Burri PH, Sehovic S. The adaptive response of the rat lung after bilobectomy. Am Rev Respir Dis 1979;119:769-777.
94. Hsia CCW, Fryder-Doffey F, Stalder-Navarro V, Johnson RL Jr, Weibel ER. Structural changes underlying compensatory increase of diffusing capacity after left pneumonectomy in adult dogs. J Clin Invest 1993;92: 758-764. [Published erratum appears in J Clin Invest 1994;93:913].
95. Hsia CCW, Herazo LF, Fryder-Doffey F, Weibel ER. Compensatory lung growth occurs in adult dogs after right pneumonectomy. J Clin Invest 1994;94:405-412.
96. Takeda S, Ramanathan M, Wu EY, Estrera AS, Hsia CCW. Temporal course of gas exchange and mechanical compensation after right pneumonectomy in immature dogs. J Appl Physiol 1996;80:1304-1312. [Published corrigenda appears in J Appl Physiol 1996;80: frontmatter].
97. Hsia CCW, Carlin JI, Wagner PD, Cassidy SS, Johnson RL Jr. Gas exchange abnormalities after pneumonectomy in conditioned fox-hounds. J Appl Physiol 1990;68:94-104.
98. Hsia CCW, Ramanathan M, Estrera AS. Recruitment of diffusing capacity with exercise in patients after pneumonectomy. Am Rev Respir Dis 1992;145:811-816.
99. Hsia CCW, Herazo LF, Ramanathan M, Johnson RL Jr, Wagner PD. Cardiopulmonary adaptations to pneumonectomy in dogs: II: ventilation-perfusion relationships and microvascular recruitment. J Appl Physiol 1993;74:1299-1309.
100. Sritippayawan S, Keens TG, Horn MV, MacLaughlin EF, Barr ML, Starnes VA, Woo MS. Does lung growth occur when mature lobes are transplanted into children? Pediatr Transplant 2002;6:500-504.
101. Binns OA, DeLima NF, Buchanan SA, Lopes MB, Cope JT, Marek CA, King RC, Laubach VE, Tribble CG, Kron IL. Mature pulmonary lobar transplants grow in an immature environment. J Thorac Cardiovasc Surg 1997;114:186-194.
102. Kern JA, Tribble CG, Flanagan TL, Chan BB, Scott WW, Cassada DC, Kron IL. Growth potential of porcine reduced-size mature pulmonary lobar transplants. J Thorac Cardiovasc Surg 1992;104:1329-1332.
103. Hislop AA, Lee RJ, McGregor CG, Haworth SG. Lung growth after transplantation of an adult lobe of lung into a juvenile rat. J Thorac Cardiovasc Surg 1998;115:644-651.
104. Ibla JC, Shamberger RC, DiCanzio J, Zurakowski D, Koka BV, Lillehei CW. Lung growth after reduced size transplantation in a sheep model. Transplantation 1999;67:233-240.
105. Kaza AK, Cope JT, Fiser SM, Long SM, Kern JA, Tribble CG, Kron IL, Laubach VE. Contrasting natures of lung growth after transplantation and lobectomy. J Thorac Cardiovasc Surg 2002;123:288-294.
106. Duebener LF, Takahashi Y, Wada H, Tschanz SA, Burri PH, Schafers HJ. Do mature pulmonary lobes grow after transplantation into an immature recipient? Ann Thorac Surg 1999;68:1165-1170.
107. Niermeyer S, Yang P. Shanmina, Drolkar, Zhuang J, Moore LG. Arterial oxygen saturation in Tibetan and Han infants born in Lhasa, Tibet. N Engl J Med 1995;333:1248-1252.
108. Schutte JE, Lilljeqvisl RE, Johnson RL Jr. Growth of lowland native children of European ancestry during sojourn at high altitude (3,200 m). Am J Phys Anthropol 1983;61:221-226.
109. Frisancho AR, Newman MT, Baker P. Differences in stature and cortical thickness among highland Quechua Indian boys. Am J Clin Nutr 1970;23:382-385.
110. Droma TS, McCullough RG, McCullough RE, Zhuang JG, Cymerman A, Sun SF, Sutton JR, Moore LG. Increased vital and total lung capacities in Tibetan compared to Han residents of Lhasa (3,658 m). Am J Phys Anthropol 1991;86:341-351.
111. Brody JS, Lahiri S, Simpser M, Motoyama EK, Velasquez T. Lung elasticity and airway dynamics in Peruvian natives to high altitude. J Appl Physiol 1977;42:245-251.
112. Frisancho AR. Human growth and pulmonary function of a high altitude Peruvian Quechua population. Hum Biol 1969;41:364-379.
113. Lahiri S, DeLaney RG, Brody JS, Simpser M, Velasquez T, Motoyama EK, Polgar C. Relative role of environmental and genetic factors in respiratory adaptation to high altitude. Nature 1976;261:133-135.
114. Frisancho AR. Developmental adaptation to high altitude hypoxia. Int J Biometeorol 1977;21:135-146.
115. Harrison GA, Kuchemann EF, Moore MAS, Boyce AJ, Baju T, Mourant AE, Godber MJ, Glasgow BG, Kopec AC, Tills D, Clegg EJ. The effects of altitude variation in Ethiopian populations. Philos Trans R Soc Land B Biol Sci 1969;256:147-182.
116. DeGraff AC Jr, Grover RF, Johnson RL Jr, Hammond JW Jr, Miller JM. Diffusing capacity of the lung in Caucasians native to 3,100 m. J Appl Physiol 1970;29:71-76.
117. Remmers JE, Mithoefer JC. The carbon monoxide diffusing capacity in permanent residents at high altitudes. Respir Physiol 1969;6:233-244.
118. Feder ME, Burggren WW. Skin breathing in vertebrates. Sci Am 1985;253:126-142.
119. Burggren W, Mwalukoma A. Respiration during chronic hypoxia and hyperoxia in larval and adult bullfrogs (Rana catesbeiana). J Exp Biol 1983;105:191-203.
120. de Grauw TJ, Myers RE, Scott WJ. Fetal growth retardation in rats from different levels of hypoxia. Biol Neonate 1986;49:85-89.
121. Pearson OP, Pearson A. A stereological analysis of the ultrastructure of the lungs of wild mice living at low and high altitude. J Morphol 1976;150:359-368.
122. Burri PH, Weibel ER. Morphometric estimation of pulmonary diffusion capacity: II: effect of Po^sub 2^ on the growing lung, adaptation of the growing rat lung to hypoxia and hyperoxia. Respir Physiol 1971;11: 247-264.
123. Bartlett D Jr. Postnatal growth of the mammalian lung: influence of low and high oxygen tensions. Respir Physiol 1970;9:58-64.
124. Bartlett D Jr, Remmers JE. Effects of high altitude on the lungs of young rats. Respir Physiol 1971;13:116-125.
125. Cunningham EL, Brody JS, Jain BP. Lung growth induced by hypoxia. J Appl Physiol 1974;37:362-366.
126. Sekhon HS, Thurlbeck WM. Lung morphometric changes after exposure to hypobaria and/or hypoxia and undernutrition. Respir Physiol 1996;106:99-107.
127. Sekhon HS, Thurlbeck WM. Time course of lung growth following exposure to hypobaria and/or hypoxia in rats. Respir Physiol 1996;105:241-252.
128. Hunter C, Barer GR, Shaw JW, Clegg EJ. Growth of the heart and lungs in hypoxic rodents: a model of human hypoxic disease. Clin Sci Mol Med 1973;46:375-391.
129. Blanco LN, Massaro D, Massaro GD. Alveolar size, number, and surface area: developmentally dependent response to 13% O2. Am J Physiol 1991;261:L370-L377.
130. Massaro GD, Olivier J, Massaro D. Short-term perinatal 10% O2 alters postnatal development of lung alveoli. Am J Physiol 1989;257:L221-L225.
131. Sekhon HS, Wright JL, Thurlbeck WM. Pulmonary function alterations after 3 wk of exposure to hypobaria and/or hypoxia in growing rats. J Appl Physiol 1995;78:1787-1792.
132. Sekhon HS, Thurlbeck WM. Lung cytokinetics after exposure to hypobaria and/or hypoxia and undernutrition in growing rats. J Appl Physiol 1995;79:1299-1309.
133. Sekhon HS, Smith C, Thurlbeck WM. Effect of hypoxia and hyperoxia on postpneumonectomy compensatory lung growth. Exp Lung Res 1993;19:519-532.
134. Gonzalez NC, Clancy RL, Wagner PD. Determinants of maximal oxygen uptake in rats acclimatized to simulated altitude. J Appl Physiol 1993;75:1608-1614.
135. Rabinovitch M, Gamble WJ, Miettinen OS, Reid L. Age and sex influence on pulmonary hypertension of chronic hypoxia and on recovery. Am J Physiol 1981;240:H62-H72.
136. Lechner AJ, Banchero N. Lung morphometry in guinea pigs acclimated to hypoxia during growth. Respir Physiol 1980;42:155-169.
137. Johnson RL Jr, Cassidy SS, Grover RF, Schutte JE, Epstein RH. Functional capacities of lungs and thorax in beagles after prolonged residence at 3,100 m. J Appl Physiol 1985;59:1773-1782.
138. Lechner AJ, Blake CI, Banchero N. Pulmonary development in growing guinea pigs exposed to chronic hypercapnia. Respiration 1987;52:108-114.
139. Grover RF, Johnson RL Jr, McCullough RG, McCullough RE, Hofmeister SE, Campbell WB, Reynolds RC. Pulmonary hypertension and pulmonary vascular reactivity in beagles at high altitude. J Appl Physiol 1988;65:2632-2640.
140. Gumbiner BM. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell 1996;84:345-357.
141. Sannes PL, Wang J. Basement membranes and pulmonary development. Exp Lung Res 1997;23:101-108.
142. Warburlon D, Schwarz M, Tefft D, Flores-Delgado G, Anderson KD, Cardoso WV. The molecular basis of lung morphogenesis. Mech Dev 2000;92:55-81.
143. Bruce MC, Honaker CE. Transcriptional regulation of tropoelastin expression in rat lung fibroblasts: changes with age and hyperoxia. Am J Physiol 1998;274:L940-L950.
144. Willet KE, McMenamin P, Pinkerton KE, Ikegami M, Jobe AH, Gurrin L, Sly PD. Lung morphometry and collagen and elastin content: changes during normal development and after prenatal hormone exposure in sheep. Pediatr Res 1999;45:615-625.
145. Ramirez F. Pathophysiology of the microfibril/elastic fiber system: introduction. Matrix Biol 2000;19:455-456.
146. Mariani TJ, Sandefur S, Pierce RA. Elastin in lung development. Exp Lung Res 1997;23:131-145.
147. Mecham RP. Elastic fibers. In: Crystal RG, Barnes PJ, West JB, Weibel ER, editors. The lung: scientific foundations. Philadelphia: Lippincott-Raven; 1997. p. 729-736.
148. Wood JP, Kolassa JE, McBride JT. Changes in alveolar septal border lengths with postnatal lung growth. Am J Physiol 1998;275:L1157-L1163.
149. Nakamura T, Liu M, Mourgeon E, Slutsky A, Post M. Mechanical strain and dexamethasone selectively increase surfactant protein C and tro poelastin gene expression. Am J Physiol Lung Cell Mol Physiol 2000;278:L974-L980.
150. McGowan SE, Jackson SK, Olson PJ, Parekh T, Gold LI. Exogenous and endogenous transforming growth factors-beta influence elastin gene expression in cultured lung fibroblasts. Am J Respir Cell Mol Biol 1997;17:25-35.
151. Brettell LM, McGowan SE. Basic fibroblast growth factor decreases elastin production by neonatal rat lung fibroblasts. Am J Respir Cell Mol Biol 1994;10:306-315.
152. Das RM. The effect of beta-aminopropionitrile on lung development in the rat. Am J Pathol 1980;101:711-722.
153. Kida K, Thurlbeck WM. Lack of recovery of lung structure and function after the administration of beta-amino-propionitrile in the postnatal period. Am Rev Respir Dis 1980;122:467-475.
154. Bruce MC, Pawlowski R, Tomashefski JF Jr. Changes in lung elastic fiber structure and concentration associated with hyperoxic exposure in the developing rat lung. Am Rev Respir Dis 1989;140:1067-1074.
155. Bruce MC, Bruce EN, Janiga K, Chetty A. Hyperoxic exposure of developing rat lung decreases tropoelastin mRNA levels that rebound postexposure. Am J Physiol 1993;265:L293-L300.
156. Bostrom H, Willetts K, Pekny M, Leveen P, Lindahl P, Hedstrand H, Pekna M, Hellstrom M, Gebre-Medhin S, Schalling M, et al. PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis. Cell 1996;85:863-873.
157. Lindahl P, Karlsson L, Hellstrom M, Gebre-Medhin S, Willetts K, Heath JK, Betsholtz C. Alveogenesis failure in PDGF-A-deficient mice is coupled to lack of distal spreading of alveolar smooth muscle cell progenitors during lung development. Development 1997;124:3943-3953.
158. Wendel DP, Taylor DG, Albertine KH, Keating MT, Li DY. Impaired distal airway development in mice lacking elastin. Am J Respir Cell Mol Biol 2000;23:320-326.
159. Massaro GD, Massaro D. Retinoic acid treatment partially rescues failed septation in rats and in mice. Am J Physiol Lung Cell Mol Physiol 2000;278:L955-L960.
160. McGowan SE, Doro MM, Jackson SK. Endogenous retinoids increase perinatal elastin gene expression in rat lung fibroblasts and fetal expiants. Am J Physiol 1997;273:L410-L416.
161. McGowan S, Jackson SK, Jenkins-Moore M, Dai HH, Chambon P, Snyder JM. Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers. Am J Respir Cell Mol Biol 2000;23:162-167.
162. McGowan SE, Torday JS. The pulmonary lipofibroblast (lipid interstitial cell) and its contributions to alveolar development. Annu Rev Physiol 1997;59:43-62.
163. Bruce MC, Honaker CE, Cross RJ. Lung fibroblasts undergo apoptosis following alveolarization. Am J Respir Cell Mol Biol 1999;20:228-236.
164. McGowan SE. Extracellular matrix and the regulation of lung development and repair. FASEB J 1992;6:2895-2904.
165. Oldmixon EH, Butler JP, Hoppin FG Jr. Lengths and topology of alveolar septal borders. J Appl Physiol 1989;67:1930-1940.
166. Butler JP, Oldmixon EH, Hoppin FG Jr. Dihedral angles of septal "bend" structures in lung parenchyma. J Appl Physiol 1996;81:1800-1806.
167. Northway WH Jr. An introduction to bronchopulmonary dysplasia. Clin Perinatal 1992;19:489-495.
168. Pierce RA, Albertine KH, Starcher BC, Bohnsack JF, Carlton DP, Bland RD. Chronic lung injury in preterm lambs: disordered pulmonary elastin deposition. Am J Physiol 1997;272:L452-L460.
169. Bruce MC, Wedig KE, Jentoft N, Martin RJ, Cheng PW, Boat TF, Fanaroff AA. Altered urinary excretion of elastin cross-links in premature infants who develop bronchopulmonary dysplasia. Am Rev Respir Dis 1985;131:568-572.
170. Bruce MC, Schuyler M, Martin RJ, Starcher BC, Tomashefski JF Jr, Wedig KE. Risk factors for the degradation of lung elastic fibers in the ventilated neonate: implications for impaired lung development in bronchopulmonary dysplasia. Am Rev Respir Dis 1992;146:204-212.
171. Shapiro SD, Endicott SK, Province MA, Pierce JA, Campbell EJ. Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radio-carbon. J Clin Invest 1991;87:1828-1834.
172. Shapiro SD. The pathogenesis of emphysema: the clastase:antielastase hypothesis 30 years later. Proc Assoc Am Physicians 1995;107:346352.
173. Shapiro SD, Senior RM. Matrix metalloproteinases: matrix degradation and more. Am J Respir Cell Mol Biol 1999;20:1100-1102.
174. Roman J, McDonald JA. Expression of fibronectin, the integrin alpha 5, and alpha-smooth muscle actin in heart and lung development. Am J Respir Cell Mol Biol 1992;6:472-480.
175. Sakai T, Larsen M, Yamada KM. Fibronectin requirement in branching morphogenesis. Nature 2003;423:876-881.
176. Wagner TE, Frevert CW, Herzog EL, Schnapp LM. Expression of the integrin subunit alpha8 in murine lung development. J Histochem Cytochem 2003;51:1307-1315.
177. Fisher JM, Simnett JD. Morphogenctic and proliferative changes in the regenerating lung of the rat. Anal Rec 1973;176:389-396.
178. Olson LE, Huffman EA. Lung volumes and distribution of regional air content determined by cine x-ray CT of pneumonectomized rabbits. J Appl Physiol 1994;76:1774-1785.
179. Wu EY, Hsia CC, Estrera AS, Epstein RH, Ramanathan M, Johnson RL Jr. Preventing mediastinal shift after pneumonectomy does not abolish physiologic compensation. J Appl Physiol 2000;89:182-191.
180. Hsia CCW, Wu EY, Wagner E, Weibel ER. Preventing mediastinal shift after pneumonectomy impairs regenerative alveolar tissue growth. Am J Physiol Lung Cell Mol Physiol 2001;281:L1279-L1287.
181. Haworth SG, McKenzie SA, Fitzpatrick ML. Alveolar development after ligation of left pulmonary artery in newborn pig: clinical relevance to unilateral pulmonary artery. Thorax 1981;36:938-943.
182. Burrows B, Harrison RW, Adams WE, Humphreys EM, Long ET. The postpneumonectomy state: clinical and physiologic observations in thirty-six cases. Am J Med 1960;28:281-297.
183. Hsia CCW, Carlin JI, Cassidy SS, Ramanathan M, Johnson RL Jr. Hemodynamic changes after pneumonectomy in the exercising fox-hound. J Appl Physiol 1990;69:51-57.
184. Takeda S, Ramanathan M, Estrera AS, Hsia CCW. Postpneumonectomy alveolar growth does not normalize hemodynamic and mechanical function. J Appl Physiol 1999;87:491-497.
185. Hsia CCW, Herazo LF, Ramanathan M, Johnson RL Jr. Cardiopulmonary adaptations to pneumonectomy in dogs: IV: membrane diffusing capacity and capillary blood volume. J Appl Physiol 1994;77:998-1005.
186. McBride JT, Kirchner KK, Russ G, Finkelstein J. Role of pulmonary blood flow in postpneumonectomy lung growth. J Appl Physiol 1992;73:2448-2451.
187. Janicki JS, Weber KT, Likoff MJ, Fishman AP. The pressure-flow response of the pulmonary circulation in patients with heart failure and pulmonary vascular disease. Circulation 1985;72:1270-1278.
188. Szlachcic J, Massie BM, Kramer BL, Topic N, Tubau J. Correlates and prognostic implication of exercise capacity in chronic congestive heart failure. Am J Cardiol 1985;55:1037-1042.
189. Townsley MI. Hydrostatic pulmonary edema. In: Matthay MA, Ingbar DH, editors. Pulmonary edema. New York: Marcel Dekker; 1998. p. 163-202.
190. Guyton AC, Lindsey AW. Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circ Res 1959;7:649-657.
191. Witte MH, Dumont AE, Clauss RH, Rader B, Levine N, Breed ES. Lymph circulation in congestive heart failure: effect of external thoracic duct drainage. Circulation 1969;39:723-733.
192. Townsley MI, Pitts VH, Ardell JL, Zhao Z, Johnson WH Jr. Altered pulmonary microvascular reactivity to norepinephrinc in canine pacing-induced heart failure. Circ Res 1994;75:347-356.
193. Herman PG, Khan A, Kallman CE, Rojas KA, Carmody DP, Bodenheimer MM. Limited correlation of left ventricular end-diastolic pressure with radiographic assessment of pulmonary hemodynamics. Radiology 1990;174:721-724.
194. Wood P. An appreciation of mitral stenosis: part II: investigations and results. BMJ 1954;4870:1113-1124.
195. Huang W, Kingsbury MP, Turner MA, Donnelly JL, Flores NA, Sheridan DJ. Capillary filtration is reduced in lungs adapted to chronic heart failure: morphological and haemodynamic correlates. Cardiovusc Res 2001;49:207-217.
196. Townsley MI, Fu Z, Mathieu-Costello O, West JB. Pulmonary microvascular permeability: responses to high vascular pressure after induction of pacing-induced heart failure in dogs. Circ Res 1995;77:317-325.
197. Lee YS. Electron microscopic studies on the alveolar-capillary barrier in the patients of chronic pulmonary edema. Jpn Circ J 1979;43:945-954.
198. Parker JC, Ivey CL, Tucker JA. Gadolinium prevents high airway pressure-induced permeability increases in isolated rat lungs. J Appl Physiol 1998;84:1113-1118.
199. Roy BJ, Pitts VH, Townsley MI. Pulmonary vascular response to angiotensin II in canine pacing-induced heart failure. Am J Physiol 1996; 271:H222-H227.
200. Ivey CL, Roy BJ, Townsley MI. Ablation of lung endothclial injury after pacing-induced heart failure is related to alterations in Ca^sup 2+^ signaling. Am J Physiol 1998;275:H844-H851.
201. Guazzi M. Alveolar-capillary membrane dysfunction in chronic heart failure: pathophysiology and therapeutic implications. Clin Sci (Lond) 2000;98:633-641.
202. Puri S, Baker BL, Dutka DP, Oakley CM, Hughes JM, Cleland JG. Reduced alveolar-capillary membrane diffusing capacity in chronic heart failure: its pathophysiological relevance and relationship to exercise performance. Circulation 1995;91:2769-2774.
203. Townsley MI, Snell KS, Ivey CL, Culberson DE, Liu DC, Reed RK, Mathieu-Costello O. Remodeling of lung interstilium but not resistance vessels in canine pacing-induced heart failure. J Appl Physiol 1999;87:1823-1830.
204. Driss AB, Devaux C, Henrion D, Duriez M, Thuillez C, Levy BI, Michel JB. Hemodynamic stresses induce endothclial dysfunction and remodeling of pulmonary artery in experimental compensated heart failure. Circulation 2000;101:2764-2770.
205. Grossman W, Braunwald E. Pulmonary hypertension. In: Braunwald E, editor. Heart disease: a textbook of cardiovascular medicine, 3rd ed. Philadelphia: W.B. Saunders; 1998. p. 793-817.
206. Aukland K, Reed RK. Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev 1993;73:1-78.
207. Laine GA, Allen SJ. Left ventricular myocardial edema: lymph flow, interstitial fibrosis, and cardiac function. Circ Res 1991;68:1713-1721.
208. Townsley MI, Reed RK, Ishibashi M, Parker JC, Laurent TC, Taylor AE. Hyaluronan efflux from canine lung with increased hydrostatic pressure and saline loading. Am J Respir Crit Care Med 1994;150:1605-1611.
209. Ivey CL, Stephenson AH, Townsley MI. Involvement of cytochrome P-450 enzyme activity in the control of microvascular permeability in canine lung. Am J Physiol 1998;275:L756-L763.
210. Bensadoun ES, Burke AK, Hogg JC, Roberts CR. Proteoglycan deposition in pulmonary fibrosis. Am J Respir Crit Care Med 1996;154:1819-1828.
211. Klappacher G, Franzen P, Haab D, Mehrabi M, Binder M, Plesch K, Pacher R, Grimm M, Pribill I, Eichler HG, et al. Measuring extracellular matrix turnover in the serum of patients with idiopathic or ischemic dilated cardiomyopalhy and impact on diagnosis and prognosis. Am J Cardiol 1995;75:913-918.
212. Sato Y, Kataoka K, Matsumori A, Sasayama S, Yamada T, Ito H, Takatsu Y. Measuring serum aminoterminal type III procollagen peptide, 7S domain of type IV collagen, and cardiac troponin T in patients with idiopathic dilated cardiomyopathy and secondary cardiomyopalhy. Heart 1997;78:505-508.
213. Breen EC. Mechanical strain increases type I collagen expression in pulmonary fibroblasls in vitro. J Appl Physiol 2000;88:203-209.
214. Parker JC, Breen EC, West JB. High vascular and airway pressures increase interstitial protein mRNA expression in isolated rat lungs. J Appl Physiol 1997;83:1697-1705.
215. Miserocchi G, Negrini D, Passi A, De Luca G. Development of lung edema: interstitial fluid dynamics and molecular structure. News Physiol Sci 2001;16:66-71.
216. Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest 2000;105:21-34.
217. Rosenberg HC, Rabinovitch M. Endothelial injury and vascular reactivity in monocrotaline pulmonary hypertension. Am J Physiol 1988; 255:H1484-H1491.
218. Yoshida M, Westlin WF, Wang N, Ingber DE, Rosenzweig A, Resnick N, Gimbrone MA Jr. Leukocyte adhesion to vascular endothelium induces E-selectin linkage to the actin cyloskeleton. J Cell Biol 1996;133:445-455.
219. Potard US, Butler JP, Wang N. Cytoskcletal mechanics in confluent epithelial cells probed through integrins and E-cadherins. Am J Physiol 1997;272:C1654-C1663.
220. Ezzell RM, Goldmann WH, Wang N, Parasharama N, higher DE. Vinculin promotes cell spreading by mechanically coupling integrins to the cytoskelelon. Exp Cell Res 1997;231:14-26.
221. Goldmann WH, Galneder R, Ludwig M, Xu W, Adamson ED, Wang N, Ezzell RM. Differences in elasticity of vinculin-deficient F9 cells measured by magnetometry and atomic force microscopy. Exp Cell Res 1998;239:235-242.
222. Alenghat FJ, Fabry B, Tsai KY, Goldmann WH, Ingber DE. Analysis of cell mechanics in single vinculin-deficient cells using a magnetic tweezer. Biochem Biophys Res Commun 2000;277:93-99.
223. Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992;69:11-25.
224. Burridge K, Path K, Kelly T, Nuckolls G, Turner C. Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. Annu Rev Cell Biol 1988;4:487-525.
225. Wang N, Butler JP, Ingber DE. Mechanotransduction across the cell surface and through the cytoskeleton. Science 1993;260:1124-1127.
226. Wang N, Ingber DE. Control of cytoskeletal mechanics by extracellular matrix, cell shape, and mechanical tension. Biophys J 1994;66:2181-2189.
227. Schmidt C, Pommerenke H, Durr F, Nebe B, Rychly J. Mechanical stressing of integrin receptors induces enhanced tyrosine phosphorylation of cytoskeletally anchored proteins. J Biol Chem 1998;273:5081-5085.
228. Meyer CJ, Alenghat FJ, Rim P, Fong JH, Fabry B, Ingber DE. Mechanical control of cyclic AMP signalling and gene transcription through inlegrins. Nat Cell Biol 2000;2:666-668.
229. Chen J, Fabry B, Schiffrin EL, Wang N. Twisting integrin receptors increases endothelin-1 gene expression in endothelial cells. Am J Physiol Cell Physiol 2001;280:C1475-C1484.
230. Chicurel ME, Chen CS, Ingber DE. Cellular control lies in the balance of forces. Curr Opin Cell Biol 1998;10:232-239.
231. Zhu C, Bao G, Wang N. Cell mechanics: mechanical response, cell adhesion, and molecular deformation. Annu Rev Blamed Eng 2000;2: 189-226.
232. Wang N. Mechanical interactions among cytoskeletal filaments. Hypertension 1998;32:162-165.
233. Fuller RB. Tensegrity. Portfolio Artnews Annual 1916;4:112-127.
234. Ingber DE. Opposing views on tensegrily as a structural framework for understanding cell mechanics. J Appi Physiol 2000;89:1663-1670.
235. Wang N, Naruse K, Stamenovic D, Fredberg JJ, Mijailovich SM, TolicNorrelykke IM, Polte T, Mannix R, Ingber DE. Mechanical behavior in living cells consistent with the tensegrity model. Proc Natl Acad Sci USA 2001;98:7765-7770.
236. Stamenovic D, Wang N. Invited review: engineering approaches to cytoskeletal mechanics. J Appl Physiol 2000;89:2085-2090.
237. Hubmayr RD, Shore SA, Fredberg JJ, Planus E, Panettieri RA Jr, Moller W, Heyder J, Wang N. Pharmacological activation changes stiffness of cultured human airway smooth muscle cells. Am J Physiol 1996;271:C1660-C1668.
238. Lee KM, Tsai KY, Wang N, Ingber DE. Extracellular matrix and pulmonary hypertension: control of vascular smooth muscle cell contractility. Am J Physiol 1998;274:H76-H82.
239. Wang N, Tolic-Norrelykke IM, Chen J, Mijailovich SM, Butler JP, Fredberg JJ, Stamenovic D. Cell prestress: I: stiffness and prestress are closely associated in adherent contractile cells. Am J Physiol Cell Physiol 2002;282:C606-C616.
240. Pourati J, Maniotis A, Spiegel D, Schaffer JL, Buller JP, Fredberg JJ, Ingber DE, Stamenovic D, Wang N. Is cytoskeletal tension a major determinant of cell deformabilily in adherent endothelial cells? Am J Physiol 1998;274:C1283-C1289.
241. Chen CS, Mrksich M, Huang S, Whitesides GM, Ingber DE. Geometric control of cell life and death. Science J997;276:1425-1428.
242. Wang N, Ostuni E, Whitesides GM, Ingber DE. Micropatterning tractional forces in living cells. Cell Motil Cytoskeleton 2002;52:97-106.
243. Kessler D, Dethlefsen S, Haase I, Plomann M, Hirche F, Krieg T, Eckes B. Fibroblasls in mechanically stressed collagen lattices assume a "synthetic" phenotype. J Biol Chem 2001;276:36575-36585.
244. Wang HB, Dembo M, Wang YL. Substrate flexibility regulates growth and apoptosis of normal but not transformed cells. Am J Physiol Cell Physiol 2000;279:C1345-C1350.
245. Brody JS, Fisher AB, Gocmen A, DuBois AB. Acromegalic pneumonomegaly: lung growth in the adult. J Clin Invest 1970;49:1051-1060.
246. De Troyer A, Desir D, Copinschi G. Regression of lung size in adults with growth hormone deficiency. Q J Med 1980;49:329-340.
247. Garcia-Rio F, Pino JM, Diez JJ, Ruiz A, Villasante C, Villamor J. Reduction of lung distensibility in acromegaly after suppression of growth hormone hypersecretion. Am J Respir Crit Care Med 2001;164:852-857.
248. Donnelly PM, Grunstein RR, Peat JK, Woolcock AJ, Bye PT. Large lungs and growth hormone: an increased alveolar number? Eur Respir J 1995;8:938-947.
249. Bartlett D Jr. Postnatal growth of the mammalian lung: influence of excess growth hormone. Respir Physiol 1971;12:297-304.
250. Ballard PL, Ning Y, Polk D, Ikegami M, Jobe AH. Glucocorticoid regulation of surfactant components in immature lambs. Am J Physiol 1997;273:L1048-L1057.
251. Snyder JM, Rodgers HF, O'Brien JA, Mahli N, Magliato SA, Durham PL. Glucocorticoid effects on rabbit fetal lung maturation in vivo: an ultrastructural morphometric study. Anat Rec 1992;232:133-140.
252. Odom MJ, Snyder JM, Boggaram V, Mendelson CR. Glucocorticoid regulation of the major surfactant associated protein (SP-A) and its messenger ribonucleic acid and of morphological development of human fetal lung in vitro. Endocrinology 1988;123:1712-1720.
253. Tschanz SA, Burri PH. Postnatal lung development and its impairment by glucocorticoids. Pediatr Pulmonol Suppl 1997;16:247-249.
254. Veness-Meehan KA, Bottone FG Jr, Stiles AD. Effects of retinoic acid on airspace development and lung collagen in hyperoxia-exposed newborn rats. Pediatr Res 2000;48:434-444.
255. Sahebjami H, Domino M. Effects of postnatal dexamethasone treatment on development of alveoli in adult rats. Exp Lung Res 1989;15:961-973.
256. Massaro GD, Massaro D. Postnatal treatment with retinoic acid increases the number of pulmonary alveoli in rats. Am J Physiol 1996;270:L305-L310.
257. Fayon M, Jouvencel P, Carles D, Choukroun ML, Marthan R. Differential effect of dexamethasone and hydrocortisone on alveolar growth in rat pups. Pediatr Pulmonol 2002;33:443-448.
258. Massaro D, Massaro GD. Dexamethasone accelerates postnatal alveolar wall thinning and alters wall composition. Am J Physiol 1986;251:R218-R224.
259. Massaro D, Teich N, Maxwell S, Massaro GD, Whitney P. Postnatal development of alveoli: regulation and evidence for a critical period in rats. J Clin Invest 1985;76:1297-1305.
260. Saarela T, Risteli J, Koivisto M. Effects of short-term dexamethasone treatment on collagen synthesis and degradation markers in preterm infants with developing lung disease. Acta Paediatr 2003;92:588-594.
261. Pierce RA, Maricncheck WI, Sandefur S, Crouch EC, Parks WC. Glucocorticoids upregulate tropoelastin expression during late stages of fetal lung development. Am J Physiol 1995;268:L491-L500.
262. Ellington B, McBride JT, Stokes DC. Effects of corticosteroids on post-natal lung and airway growth in the ferret. J Appl Physiol 1990;68:2029-2033.
263. Rannels DE, Karl HW, Bennett RA. Control of compensatory lung growth by adrenal hormones. Am J Physiol 1987;253:E343-E348.
264. Bennett RA, Addison JL, Rannels DE. Static mechanical properties of lungs from adrenalectomized pneumonectomized rats. Am J Physiol 1987;253:E6-E11.
265. Bennett RA, Colony PC, Addison JL, Rannels DE. Effects of prior adrcnalectomy on postpneumonectomy lung growth in the rat. Am J Physiol 1985;248:E70-E74.
266. Newnham JP. Is prenatal glucocorticoid administration another origin of adult disease? Clin Exp Pharmacol Physiol 2001;28:957-961.
267. O'Shea TM, Doyle LW. Perinatal glucocorticoid therapy and neuro-developmental outcome: an epidemiologic perspective. Semin Neonatal 2001;6:293-307.
268. Faridy EE, Sanii MR, Thliveris JA. Influence of maternal pneumonectomy on fetal lung growth. Respir Physiol 1988;72:195-209.
269. Thurlbeck WM, D-Ercole AJ, Smith BT. Serum somatomedin C concentrations following pneumonectomy. Am Rev Respir Dis 1984;130:499500.
270. Khadempour MH, Ofulue AF, Sekhon HS, Cherukupalli KM, Thurlbeck WM. Changes of growth hormone, somatomedin C, and bombesin following pneumonectomy. Exp Lung Res 1992;18:421-432.
271. Nobuhara KK, DiFiore JW, Ibla JC, Siddiqui AM, Ferretti ML, Fauza DO, Schnitzer JJ, Wilson JM. Insulin-like growth faclor-I gene expression in three models of accelerated lung growth. J Pediatr Surg 1998; 33:1057-60; discussion 1061.
272. McAnulty RJ, Guerreiro D, Cambrey AD, Laurent GJ. Growth factor activity in the lung during compensatory growth after pneumonectomy: evidence of a role for IGF-1. Eur Respir J 1992;5:739-747.
273. Miettinen PJ, Warburton D, Bu D, Zhao JS, Berger JE, Minoo P, Koivisto T, Allen L, Dobbs L, Werb Z, et al. Impaired lung branching morphogenesis in the absence of functional EGF receptor. Dev Biol 1997;186:224-236.
274. Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, LaMantia C, Mourton T, Herrup K, Harris RC, et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 1995;269:230-234.
275. Catterton WZ, Escobedo MB, Sexson WR, Gray ME, Sundell HW, Stahlman MT. Effect of epidermal growth factor on lung maturation in fetal rabbits. Pediatr Res 1979;13:104-108.
276. Henck JW, Reindel JF, Anderson JA. Growth and development in rats given recombinant human epidermal growth factor(1-48) as neonates. Toxicol Sci 2001;62:80-91.
277. Foster DJ, Van X, Bellotto DJ, Moe OW, Hagler HK, Estrera AS, Hsia CCW. Expression of epidermal growth factor and surfactant proteins during postnatal and compensatory lung growth. Am J Physiol Lung Cell Mol Physiol 2002;283:L981-L990.
278. Kaza AK, Kron IL, Long SM, Fiser SM, Stevens PM, Kern JA, Tribble CG, Laubach VE. Epidermal growth factor receptor up-regulation is associated with lung growth after lobectomy. Ann Thorac Surg 2001;72:380-385.
279. Kaza AK, Laubach VE, Kern JA, Long SM, Fiser SM, Tepper JA, Nguyen RP, Shockey KS, Tribble CG, Kron IL. Epidermal growth factor augments postpneumonectomy lung growth. J Thorac Cardiovasc Surg 2000;120:916-921.
280. Yoshimura S, Masuzaki H, Miura K, Gotoh H, Moriyama S, Fujishita A, Ishimaru T. Effect of epidermal growth factor on lung growth in experimental fetal pulmonary hypoplasia. Early Hum Dev 2000;57:61-69.
281. Simonet WS, DeRose ML, Bucay N, Nguyen HQ, Wert SE, Zhou L, Ulich TR, Thomason A, Danilenko DM, Whilsett JA. Pulmonary malformation in transgenic mice expressing human keratinocyte growth factor in the lung. Proc Natl Acad Sci USA 1995;92:12461-12465.
282. Peters K, Werner S, Liao X, Wert S, Whitsett J, Williams L. Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung. EMBO J 1994;13:3296-3301.
283. Guo L, Degenstein L, Fuchs E. Keratinocyte growth factor is required for hair development but not for wound healing. Genes Dev 1996;10:165-175.
284. Min H, Danilenko DM, Scully SA, Bolon B, Ring BD, Tarpley JE, DeRose M, Simonet WS. Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev 1998;12:3156-3161.
285. Ulich TR, Yi ES, Longmuir K, Yin S, Biltz R, Morris CF, Housley RM, Pierce GF. Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo. J Clin Invest 1994;93:1298-1306.
286. Chelly N, Mouhieddine-Gueddiche OB, Barlier-Mur AM, Chailley-Heu B, Bourbon JR. Keratinocyte growth factor enhances maturation of fetal rat lung type II cells. Am J Respir Cell Mol BM 1999;20:423-432.
287. Prince LS, Karp PH, Moninger TO, Welsh MJ. KGF alters gene expression in human airway epithelia: potential regulation of the inflammatory response. Physiol Genomics 2001;6:81-89.
288. Panos RJ, Bak PM, Simonet WS, Rubin JS, Smith LJ. Intratracheal instillation of keratinocyte growth factor decreases hyperoxia-induced mortality in rats. J Clin Invest 1995;96:2026-2033.
289. Frank L. Protective effect of keratinocyte growth factor against lung abnormalities associated with hyperoxia in prematurely born rats. Biol Neonate 2003;83:263-272.
290. Sugahara K, Iyama K, Kuroda MJ, Sano K. Double intratracheal instillation of keratinocyte growth factor prevents bleomycin-induced lung fibrosis in rats. J Pathol 1998;186:90-98.
291. Yi ES, Williams ST, Lee H, Malicki DM, Chin EM, Yin S, Tarpley J, Ulich TR. Keratinocyte growth factor ameliorates radiation- and bleomycin-induced lung injury and mortality. Am J Pathol 1996;149:1963-1970.
292. Yano T, Deterding RR, Simonet WS, Shannon JM, Mason RJ. Keratinocyte growth factor reduces lung damage due to acid instillation in rats. Am J Respir Cell Mol Biol 1996;15:433-442.
293. Charafeddine L, D'Angio CT, Richards JL, Stripp BR, Finkelstein JN, Orlowski CC, LoMonaco MB, Paxhia A, Ryan RM. Hyperoxia increases keratinocyte growth factor mRNA expression in neonatal rabbit lung. Am J Physiol 1999;276:L105-L113.
294. Stern JB, Fierobe L, Paugam C, Rolland C, Dehoux M, Petiet A, Dombret MC, Mantz J, Aubier M, Crestani B. Keratinocyte growth factor and hepatocyte growth factor in bronchoalveolar lavage fluid in acute respiratory distress syndrome patients. Crit Care Med 2000;28:2326-2333.
295. McCabe AJ, Carlino U, Holm BA, Glick PL. Upregulation of keratinocyte growth factor in the tracheal ligalion lamb model of congenital diaphragmatic hernia. J Pediatr Surg 2001;36:128-132.
296. Tichelaar JW, Lu W, Whitsett JA. Conditional expression of fibroblast growth factor-7 in the developing and mature lung. J Biol Chem 2000;275:11858-11864.
297. Panos RJ, Rubin JS, Csaky KG, Aaronson SA, Mason RJ. Keratinocyte growth factor and hepatocyte growth factor/scatter factor are heparin-binding growth factors for alveolar type II cells in fibroblasl-conditioned medium. J Clin Invest 1993;92:969-977. [Published erratum appears in J Clin Invest 1994;93:1347].
298. Ohmichi H, Matsumoto K, Nakamura T. In vivo mitogenic action of HGF on lung epithelial cells: pulmotrophic role in lung regeneration. Am J Physiol 1996;270:L1031-L1039.
299. Ware LB, Matthay MA. Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair. Am J Physiol Lung Cell Mol Physiol 2002;282:L924-L940.
300. Taipale J, Keski-Oja J. Hepatocyte growth factor releases epithelial and endothelial cells from growth arrest induced by transforming growth factor-betal. J Biol Chem 1996;271:4342-4348.
301. Kim HJ, Sammak PJ, Ingbar DH. Hepatocyte growth factor stimulates migration of type II alveolar epithelial cells on the provisional matrix proteins fibronectin and fibrinogen. Chest 1999;116:945-958.
302. Ohmichi H, Koshimizu U, Matsumoto K, Nakamura T. Hepatocyte growth factor (HGF) acts as a mesenchyme-derived morphogenic factor during fetal lung development. Development 1998;125:1315-1324.
303. Dohi M, Hasegawa T, Yamamoto K, Marshall BC. Hepatocyte growth factor attenuates collagen accumulation in a marine model of pulmonary fibrosis. Am J Respir Crit Care Med 2000;162:2302-2307.
304. Ono M, Sawa Y, Matsumoto K, Nakamura T, Kaneda Y, Matsuda H. In vivo gene transfection with hepatocyte growth factor via the pulmonary artery induces angiogenesis in the rat lung. Circulation 2002;106:I264-I269.
305. Sugahara K, Matsumolo M, Baba T, Nakamura T, Kawamoto T. Elevation of serum human hepatocyte growth factor (HGF) level in patients with pneumonectomy during a perioperative period. Intensive Care Med 1998;24:434-437.
306. Sakamaki Y, Matsumoto K, Mizuno S, Miyoshi S, Matsuda H, Nakamura T. Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice. Am J Respir Cell Mol Biol 2002;26:525-533.
307. Madtes DK, Busby HK, Strandjord TP, Clark JG. Expression of transforming growth factor-alpha and epidermal growth factor receptor is increased following bleomycin-induced lung injury in rats. Am J Respir Cell Mol Biol 1994;11:540-551.
308. Mann GB, Fowler KJ, Gabriel A, Nice EC, Williams RL, Dunn AR. Mice with a null mutation of the TGF alpha gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation. Cell 1993;73:249-261.
309. Korfhagen TR, Swantz RJ, Wert SE, McCarty JM, Kerlakian CB, Glasser SW, Whitsett JA. Respiratory epithelial cell expression of human transforming growth factor-alpha induces lung fibrosis in transgenic mice. J Clin Invest 1994;93:1691-1699.
310. Le Cras TD, Hardie WD, Fagan K, Whitsett JA, Korfhagen TR. Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-alpha. Am J Physiol Lung Cell Mol Physiol 2003;285:L1046-L1054.
311. Waheed S, D'Angio CT, Wagner CL, Madtes DK, Finkelstein JN, Paxhia A, Ryan RM. Transforming growth factor alpha (TGFalpha) is increased during hyperoxia and fibrosis. Exp Lung Res 2002;28:361-372.
312. Buch S, Han RN, Cabacungan J, Wang J, Yuan S, Belcastro R, Deimling J, Jankov R, Luo X, Lye SJ, et al. Changes in expression of platelet-derived growth factor and its receptors in the lungs of newborn rats exposed to air or 60% O(2). Pediatr Res 2000;48:423-433.
313. Bostrom H, Gritli-Linde A, Betsholtz C. PDGF-A/PDGF alpha-receptor signaling is required for lung growth and the formation of alveoli but not for early lung branching morphogenesis. Dev Dyn 2002;223:155-162.
314. Yuan S, Hannam V, Belcastro R, Cartel N, Cabacungan J, Wang J, Diambomba Y, Johnstone L, Post M, Tanswell AK. A role for platelet-derived growth factor-BB in ral postpneumonectomy compensatory lung growth. Pediatr Ras 2002;52:25-33.
315. Healy AM, Morgenthau L, Zhu X, Farber HW, Cardoso WV. VEGF is deposited in the subepithelial matrix at the leading edge of branching airways and stimulates neovascularization in the murine embryonic lung. Dev Dyn 2000;219:341-352.
316. Klekamp JG, Jarzecka K, Perkett EA. Exposure to hyperoxia decreases the expression of vascular endothelial growth factor and its receptors in adult rat lungs. Am J Pathol 1999;154:823-831.
317. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, Fahrig M, Vandenhoeck A, Harpal K, Eberhardt C, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996;380:435-439.
318. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS, Powell-Braxton L, Hillan KJ, Moore MW. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996;380:439-442.
319. Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, Rangell L, Wright BD, Radtke F, Aguet M, Ferrara N. VEGF is required for growth and survival in neonatal mice. Development 1999;126:1149-1159.
320. Boussat S, Eddahibi S, Coste A, Fataccioli V, Gouge M, Houssel B, Adnot S, Maitre B. Expression and regulation of vascular endothelial growth factor in human pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol 2000;279:L371-L378.
321. Klekamp JG, Jarzecka K, Hoover RL, Summar ML, Redmond N, Perkett EA. Vascular endothelial growth factor is expressed in ovine pulmonary vascular smooth muscle cells in vitro and regulated by hypoxia and dexamethasone. Pediatr Res 1997;42:744-749.
322. Muratore CS, Nguyen HT, Ziegler MM, Wilson JM. Stretch-induced upregulalion of VEGF gene expression in murine pulmonary culture: a role for angiogenesis in lung development. J Pediatr Surg 2000;35: 906-912; discussion 912-913.
323. Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995;376:66-70.
324. Brekken RA, Overholser JP, Stastny VA, Wallenberger J, Minna JD, Thorpe PE. Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice. Cancer Res 2000;60:5117-5124.
325. Compernolle V, Brusselmans K, Acker T, Hoel P, Tjwa M, Beck H, Plaisance S, Dor Y, Keshel E, Lupu F, et al. Loss of HIF-2alpha and inhibilion of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 2002;8:702-710.
326. Kumazaki K, Nakayama M, Suehara N, Wada Y. Expression of vascular endothelial growth factor, placental growth factor, and their receptors Flt-1 and KDR in human placenta under pathologic conditions. Hum Pathol 2002;33:1069-1077.
327. Ng YS, Rohan R, Sunday ME, Demello DE, D'Amore PA. Differential expression of VEGF isoforms in mouse during development and in the adult. Dev Dyn 2001 ;220:112-121.
328. Akeson AL, Greenberg JM, Cameron JE, Thompson FY, Brooks SK, Wiginton D, Whitsett JA. Temporal and spatial regulation of VEGF-A controls vascular patterning in the embryonic lung. Dev Biol 2003;264: 443-455.
329. Bhatt AJ, Amin SB, Chess PR, Walkins RH, Maniscalco WM. Expression of vascular endothelial growth factor and Flk-1 in developing and glucocorticoid-treated mouse lung. Pediatr Res 2000;47:606-613.
330. Kasahara Y, Tuder RM, Taraseviciene-Stewart L, Le Cras TD, Abman S, Hirth PK, Waltenberger J, Voelkel NF. Inhibilion of VEGF receptors causes lung cell apoplosis and emphysema. J Clin Invest 2000; 106:1311-1319.
331. Bandi N, Kompella UB. Budesonide reduces vascular endothelial growth factor secretion and expression in airway (Calu-1) and alveolar (A549) epithelial cells. Eur J Pharmacol 2001;425:109-116.
332. Maeda S, Suzuki S, Suzuki T, Endo M, Moriya T, Chida M, Kondo T, Sasano H. Analysis of intrapulmonary vessels and epithelialendothelial interactions in the human developing lung. Lab Invest 2002;82:293-301.
333. Knox AJ, Corbelt L, Slocks J, Holland E, Zhu YM, Pang L. Human airway smooth muscle cells secrete vascular endothelial growth factor: up-regulation by bradykinin via a protein kinase C and prostanoiddependent mechanism. FASEB J 2001;15:2480-2488.
334. Brown KR, England KM, Goss KL, Snyder JM, Acarregui MJ. VEGF induces airway epithelial cell proliferation in human fetal lung in vilro. Am J Physiol Lung Cell Mol Physiol 2001;281:L1001-L1010.
335. Le Cras TD, Markham NE, Tuder RM, Voelkel NF, Abman SH. Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure. Am J Physiol Lung Cell Mol Physiol 2002;283:L555-L562.
336. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y. A novel bHLH-PAS factor with close sequence similarity to hypoxiainduciblc factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development, Proc Natl Acad Sci USA 1997;94:4273-4278.
337. Hosford GE, Olson DM. Effects of hyperoxia on VEGF, its receptors, and HIF-2alpha in the newborn rat lung. Am J Physiol Lung Cell Mol Physiol 2003;285:L161-L168.
338. Perkett EA, Klekamp JG. Vascular endothelial growth factor expression is decreased in rat lung following exposure to 24 or 48 hours of hyperoxia: implications for endothelial cell survival. Chest 1998;114: 52S-53S.
339. Maeno T, Tanaka T, Sando Y, Suga T, Macno Y, Nakagawa J, HosonoT, Salo M, Akiyama H, Kishi S, et al. Stimulation of vascular endothelial growth factor gene transcription by all trans retinoic acid through Sp1 and Sp3 sites in human bronchioloalveolar carcinoma cells. Am J Respir Cell Mol Biol 2002;26:246-253.
340. Abdulmalck K, Ashur F, Ezer N, Ye F, Magder S, Hussain SN. Differential expression of Tie-2 receptors and angiopoictins in response to in vivo hypoxia in rats. Am J Physiol Lung Cell Mol Physiol 2001;281: L582-L590.
341. Colen KL, Crisera CA, Rose MI, Connelly PR, Longaker MT, Gittes GK. Vascular development in the mouse embryonic pancreas and lung. J Pediatr Surg 1999;34:781-785.
342. Chinoy MR, Graybill MM, Miller SA, Lang CM, Kauffman GL. Angiopoietin-1 and VEGF in vascular development and angiogenesis in hypoplastic lungs. Am J Physiol Lung Cell Mol Physiol 2002; 283:L60-L66.
343. Thistlethwaite PA, Lee SH, Du LL, Wolf PL, Sullivan C, Pradhan S, Deutsch R, Jamieson SW. Human angiopoictin gene expression is a marker for severity of pulmonary hypertension in patients undergoing pulmonary thromboendarlcreclomy. J Thorac Cardiovasc Surg 2001; 122:65-73.
344. Pelton RW, Johnson MD, Perkett EA, Gold LI, Moses HL. Expression of transforming growth factor-beta 1, -beta 2, and -beta 3 mRNA and protein in the murine lung. Am J Respir Cell Mol Biol 1991;5:522-530.
345. Perkett EA, Pelton RW, Meyrick B, Gold LI, Miller DA. Expression of transforming growth factor-beta mRNAs and proteins in pulmonary vascular remodeling in the sheep air embolization model of pulmonary hypertension. Am J Respir Cell Mol Biol 1994;11:16-24.
346. Botney MD, Bahadori L, Gold LI. Vascular remodeling in primary pulmonary hypertension: potential role for transforming growth factor-beta. Am J Pathol 1994;144:286-295.
347. Pertovaara L, Kaipainen A, Mustonen T, Orpana A, Ferara N, Saksela O, Alitalo K. Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem 1994;269:6271-6274.
348. Zeg X, Gray M, Stahlman MT, Whitset JA. TGF-betal perturbs vascular development and inhibits epithelial differentiation in fetal lung in vivo. Dev Dyn 2001;221:289-301.
349. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA III, Loyd JE, Nichols WC, Trebath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension: the International PPH Consortium. Nat Genet 2000;26:81-84.
350. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000; 67:737-744.
351. Morbidelli L, Chang CH, Douglas JG, Granger HJ, Ledda F, Ziehe M. Nitric oxide mediates mitogenic effect of VEGF on coronary venular endothelium. Am J Physiol 1996;270:H411-H415.
352. Lee PC, Salyapongse AN, Bragdon GA, Shears LL II, Watkins SC, Edington HD, Billiar TR. Impaired wound healing and angiogenesis in eNOS-deficient mice. Am J Physiol 1999;277:H1600-H1608.
353. Ziehe M, Morbidelli L, Choudhuri R, Zhang HT, Donnini S, Granger HJ, Bicknell R. Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. J Clin Invest 1997;99:2625-2634.
354. Pierce RL, Pierce MR, Liu H, Kadowitz PJ, Miller MJ. Limb reduction defects after prenatal inhibition of nitric oxide synthase in rats. Pediatr Res 1995;38:905-911.
355. Huang PL, Fishman MC. Genetic analysis of nitric oxide synthasc isoforms: targeted mutation in mice. J Mol Med 1996;74:415-421.
356. Balasubramaniam V, Tang JR, Maxey A, Plopper CG, Abman SH. Mild hypoxia impairs alveolarization in the endothelial nitric oxide synthase-deficient mouse. Am J Physiol Lung Cell Mol Physiol 2003; 284:L964-L971.
357. Schini-Kerth VB, Vanhoulte PM. Nitric oxide synthases in vascular cells. Exp Physiol 1995;80:885-905.
358. Diaz-Guerra MJ, Velasco M, Martin-Sanz P, Bosca L. Nuclear factor kappaB is required for the transcriptional control of type II NO synthase in regenerating liver. Blochem J 1997;326:791-797.
359. Rai RM, Lee FY, Rosen A, Yang SQ, Lin HZ, Koteish A, Liew FY, Zaragoza C, Lowenstein C, Diehl AM. Impaired liver regeneration in inducible nitric oxide synthase deficient mice, Proc Nail Acad Sci USA 1998;95:13829-13834.
360. Ofulue AF, Matsui R, Thurlbeck WM. Role of calmodulin as an endogenous initiatory factor in compensatory lung growth after pneumoneetomy. Pediatr Pulmonol 1993;15:145-150.
361. Leuwerke SM, Kaza AK, Tribble CG, Kron IL, Laubach VE. Inhibition of compensatory lung growth in endothelial nitric oxide synthasedeficient mice. Am J Physiol Lung Cell Mol Physiol 2002;282:L1272L1278.
362. Parenti A, Morbidelli L, Cui XL, Douglas JG, Hood JD, Granger HJ, Ledda F, Ziehe M. Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-regulated kinase 1/2 activation in postcapillary endothelium. J Biol Chem 1998; 273:4220-4226.
363. Singh K, Balligand JL, Fischer TA, Smith TW, Kelly RA. Regulation of cytokine-inducible nitric oxide synthase in cardiac myocytes and microvascular endothelial cells. Role of extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and STAT1 alpha. J Biol Chem 1996; 271:1111-1117.
364. Petkovich M. Regulation of gene expression by vitamin A: the role of nuclear retinoic acid receptors. Annu Rev Nutr 1992;12:443-471.
365. Marcus R, Coulston AM. Fat-soluble vitamins. In: Hardman JG, Limbird LE, editors. Goodman & Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill; 1996. p. 1573-1590.
366. George TN, Snyder JM. Regulation of surfactant protein gene expression by retinoic acid metabolites. Pediatr Res 1997;41:692-701.
367. Cardoso WV, Mitsialis SA, Brody JS, Williams MC. Retinoic acid alters the expression of pattern-related genes in the developing rat lung. Dev Dyn 1996;207:47-59.
368. Cardoso WV, Williams MC, Mitsialis SA, Joyce-Brady M, Rishi AK, Brody JS. Retinoic acid induces changes in the pattern of airway branching and alters epithelial cell differentiation in the developing lung in vitro. Am J Respir Cell Mol Biol 1995;12:464-476.
369. Chytil F. Retinoids in lung development. FASEB J 1996;10:986-992.
370. Fraslon C, Bourbon JR. Comparison of effects of epidermal and insulinlike growth factors, gastrin releasing peptide and retinoic acid on fetal lung cell growth and maturation in vitro. Biochim Biophys Acta 1992;1123:65-75.
371. Oberg KC, Soderquist AM, Carpenter G. Accumulation of epidermal growth factor receptors in retinoic acid- treated fetal rat lung cells is due to enhanced receptor synthesis. Mol Endocrinol 1988;2:959-965.
372. Schuger L, Varani J, Mitra R Jr, Gilbride K. Retinoic acid stimulates mouse lung development by a mechanism involving epithclial-mesenchymal interaction and regulation of epidermal growth factor receptors. Dev Biol 1993;159:462-473.
373. Oberg KC, Carpenter G. EGF-induced PGE2 release is synergistically enhanced in retinoic acid treated fetal rat lung cells. Blochem Biophys Res Commun 1989;162:1515-1521.
374. Federspeil SJ, DiMari SJ. Guerry-Force ML, Haralson MA. Extracellular matrix biosynthesis by cultured fetal rat lung epithelial cells: II: effects of acute exposure to epidermal growth factor and relinoic acid on collagen biosynthesis. Lab Invest 1990;63:455-466.
375. Lachgar S, Charveron M, Gall Y, Bonafe JL. Inhibitory effects of retinoids on vascular endothelial growth factor production by cultured human skin keratinocytes. Dermatology 1999;199:25-27.
376. Massaro GD, Massaro D, Chambon P. Retinoic acid receptor-alpha regulates pulmonary alveolus formation in mice after, but not during, perinatal period. Am J Physiol Lung Cell Mol Physiol 2003;284:L431-L433.
377. Massaro GD, Massaro D, Chan WY, Clerch LB, Ghyselinck N, Chambon P, Chandraratna RA. Retinoic acid receptor-beta: an endogenous inhibitor of the perinatal formation of pulmonary alveoli. Physiol Genomics 2000;4:51-57.
378. Belloni PN, Garvin L, Mao CP, Bailey-Healy I, Leaffer D. Effects of all-trans-retinoic acid in promoting alveolar repair. Chest 2000;117: 235S-241S.
379. Randell SH, Mercer RR, Young SL. Postnatal growth of pulmonary acini and alveoli in normal and oxygen-exposed rats studied by serial section reconstructions. Am J Anal 1989;186:55-68.
380. Veness-Meehan KA, Pierce RA, Moats-Staats BM, Stiles AD. Retinoic acid attenuates O2-induced inhibition of lung septation. Am J Physiol Lung Cell Mol Physiol 2002;283:L971-L980.
381. Massaro GD, Massaro D. Retinoic acid treatment abrogates elastaseinduced pulmonary emphysema in rats. Nat Med 1997;3:675-677. [Published erratum appears in Nat Med 1997;3:805].
382. Kaza AK, Kron IL, Kern JA, Long SM, Fiser SM, Nguyen RP, Tribble CG, Laubach VE. Retinoic acid enhances lung growth after pneumonectomy. Ann Thorac Surg 2001;71:1645-1650.
383. Lucey EC, Goldstein RH, Breuer R, Rexer BN, Ong DE, Snider GL. Retinoic acid does not affect alveolar septation in adult FVB mice with elastase-induced emphysema. Respiration 2003;70:200-205.
384. Tepper J, Pfeiffer J, Aldrich M, Tumas D, Kern J, Hoffman E, McLennan G, Hyde D. Can retinoic acid ameliorate the physiologic and morphologic effects of elastase instillation in the rat? Chest 2000; 117:2428-2445.
385. Yan X, Bellotto DJ, Foster DJ, Johnson Jr RL, Hagler HH, Estrera AS, Hsia CC. Retinoic acid induces non-uniform alveolar septal growth following right pneumoncctomy. J Appl Physiol 2004;96:1080-1089.
386. Dane DM, Yan X, Tamhane RM, Johnson Jr RL, Estrera AS, Hogg DC, Hogg RT, Hsia CC. Retinoic acid-induced alveolar cellular growth does not improve function following right pneumonectomy. J Appl Physiol 2004;96:1090-1096.
387. Acarregui MJ, Snyder JM, Mendelson CR. Oxygen modulates the differentiation of human fetal lung in vitro and its responsiveness to cAMP. Am 3 Physiol 1993;264:L465-L474.
388. Kourembanas S, Hannan RL, Faller DV. Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothclial cells. J Clin Invest 1990;86:670-674.
389. Babal P, Manuel SM, Oison JW, Gillespie MN. Cellular disposition of transported polyamines in hypoxic rat lung and pulmonary arteries. Am J Physiol Lung Cell Mol Physiol 2000;278:L610-L617.
390. Hoet PH, Nemery B. Polyamines in the lung: polyamine uptake and polyamine-linked pathological or toxicological conditions. Am J Physiol Lung Cell Mol Physiol 2000;278:L417-L433.
391. Graven KK, Zimmerman LH, Dickson EW, Weinhouse GL, Farber HW. Endothelial cell hypoxia associated proteins are cell and stress specific. J Cell Physiol 1993;157:544-554.
392. Zhu H, Bunn HF. Oxygen sensing and signaling: impact on the regulation of physiologically important genes. Respir Physiol 1999;115:239-247.
393. Marti HH, Risau W. Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors, Proc Natl Acad Sci USA 1998;95:15809-15814.
394. Gehling UM, Ergun S, Schumacher U, Wagener C, Pantel K, Otte M, Schuch G, Schafhausen P, Mende T, Kilic N, et al. In vitro differentiation of endothclial cells from AC133-positive progenitor cells. Blood 2000;95:3106-3112.
395. Zhang ZG, Zhang L, Jiang Q, Chopp M. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res 2002;90:284-288.
396. Ali NN, Edgar AJ, Samadikuchaksaraei A, Timson CM, Romanska HM, Polak JM, Bishop AE. Derivation of type II alveolar epithelial cells from murine embryonic stem cells. Tissue Eng 2002;8:541-550.
397. Kotton DN, Ma BY, Cardoso WV, Sanderson EA, Summer RS, Williams MC, Fine A. Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development 2001;128:5181-5188.
398. Perl AK, Wert SE, Nagy A, Lobe CG, Whitsett JA. Early restriction of peripheral and proximal cell lineages during formation of the lung. Proc Natl Acad Sci USA 2002;99:10482-10487.
399. Ten Have-Opbroek AA. Immunological study of lung development in the mouse embryo: II: first appearance of the great alveolar cell, as shown by immunofluorescence microscopy. Dev Biol 1979;69:408-423.
400. Adamson IY, Bowden DH. The type 2 cell as progenitor of alveolar epithelial regeneration: a cytodynamic study in mice after exposure to oxygen. Lab Invest 1974;30:35-42.
401. Blackburn EH, Greider CW, Henderson E, Lee MS, Shampay J, Shippen-Lentz D. Recognition and elongation of telomeres by telomerase. Genome 1989;31:553-560.
402. Greenberg RA, Allsopp RC, Chin L, Morin GB, DePinho RA. Expression of mouse telomerasc reverse transcriptase during development, differentiation and proliferation. Oncogene 1998;16:1723-1730.
403. Greider CW. Telomeres and senescence: the history, the experiment, the future. Can Biol 1998;8:R178-R181.
404. Lavker RM, Miller S, Wilson C, Cotsarelis G, Wei ZG, Yang JS, Sun TT. Hair follicle stem cells: their location, role in hair cycle, and involvement in skin tumor formation. J Invest Dermatol 1993;101: 16S-26S.
405. Paulus U, Potten CS, Loeffler M. A model of the control of cellular regeneration in the intestinal crypt after perturbation based solely on local stem cell regulation. Cell Prolif 1992;25:559-578.
406. Morrison SJ, Shah NM, Anderson DJ. Regulatory mechanisms in stem cell biology. Cell 1997;88:287-298.
407. Wuenschell CW, Sunday ME, Singh G, Minoo P, Slavkin HC, Warburton D. Embryonic mouse lung epithelial progenitor cells co-express immunohistochemical markers of diverse mature cell lineages. J Histochem Cytochem 1996;44:113-123.
408. ten Have-Opbrock AA, Otto-Verberne CJ, Dubbeldam JA, Dykman JH. The proximal border of the human respiratory unit, as shown by scanning and transmission electron microscopy and light microscopical cytochemistry. Anat Rec 1991;229:339-354.
409. Mason RJ, Williams MC, Moses HE, Mohla S, Berberich MA. Stem cells in lung development, disease, and therapy. Am J Respir Cell Mol Biol 1997; 16:355-363.
410. Evans MJ, Cabrai EJ, Stephens RJ, Freeman G. Transformation of alveolar type 2 cells to type 1 cells following exposure to NO2. Exp Mol Pathol 1975;22:142-150.
411. Driscoll B, Buckley S, Bui KC, Anderson KD, Warburton D. Telomerase in alveolar epithelial development and repair. Am J Physiol Lung Cell Mol Physiol 2000;279:L1191-L1198.
412. Kolquist KA, Ellisen EW, Counter CM, Meyerson M, Tan EK, Weinberg RA, Haber DA, Gerald WE. Expression of TERT in early premalignant lesions and a subset of cells in normal tissues. Nat Genet 1998;19:182-186.
413. Hiyama K, Hiyama E, Ishioka S, Yamakido M, Inai K, Gazdar AF, Piatyszek MA, Shay JW. Telomerase activity in small-cell and nonsmall-cell lung cancers. J Natl Cancer Inst 1995;87:895-902.
414. Buckley S, Barsky E, Driscoll B, Weinberg K, Anderson KD, Warburton D. Apoplosis and DNA damage in type 2 alveolar epithelial cells cultured from hypcroxic rats. Am J Physiol 1998;274:L714-L720.
415. Tryka AF, Witschi H, Gosslee DG, McArthur AH, Clapp NK. Patterns of cell proliferation during recovery from oxygen injury: species differences. Am Rev Respir Dis 1986;133:1055-1059.
416. Runswick SK, O'Hare MJ, Jones E, Streuli CH, Garrod DR. Desmosomal adhesion regulates epithelial morphogenesis and cell positioning. Nat Cell Biol 2001;3:823-830.
417. Smythc WR, Williams JP, Whcelock MJ, Johnson KR, Kaiser ER, Albelda SM. Cadherin and catenin expression in normal human bronchial epithelium and non-small cell lung cancer. Lung Cancer 9 1999; 24:157-168.
418. Sulzer MA, Leers MP, van Noord JA, Bollen EC, Theunissen PH. Reduced E-cadherin expression is associated with increased lymph node metastasis and unfavorable prognosis in non-small cell lung cancer. Am J Respir Crit Care Med 1998;157:1319-1323.
419. Akimoto T, Kawabe S, Grothey A, Milas E. Eow E-cadherin and betacalenin expression correlates with increased spontaneous and artificial lung metastases of murine carcinomas. Clin Exp Metastasis 1999; 17:171-176.
420. Llorens A, Rodrigo I, Eopez -Barcons E, Gonzalez-Garrigues M, Eozano E, Vinyals A, Quintanilla M, Cano A, Fabra A. Down-regulation of E-cadherin in mouse skin carcinoma cells enhances a migratory and invasive phenotype linked to matrix metalloprotcinase-9 gelatinase expression. Lab Invest 1998;78:1131-1142.
421. Reddy R, Buckley S, Doerken M, Barsky E, Weinberg K, Anderson KD, Warburton D, Driscoll B. Isolation of a putative progenitor subpopulation of alveolar epithelial type 2 cells. Am J Physiol Lung Cell Mol Physiol 2004;286:E658-E667.
422. Ofulue AF, Thurlbeck WM. Effects of streptozotocin-induced diabetes on postpneumonectomy lung growth and connective tissue levels. Pediatr Pulmonol 1995;19:365-370.
423. McAnulty RJ, Staple EH, Guerreiro D, Laurent GJ. Extensive changes in collagen synthesis and degradation during compensatory lung growth. Am J Physiol 1988;255:C754-C759.
424. Adamson IY, King GM, Bowden DH. Collagen breakdown during acute lung injury. Thorax 1988;43:562-568.
425. Hoff CR, Perkins DR, Davidson JM. Elastin gene expression is upregulated during pulmonary fibrosis. Connect Tissue Res 1999;40:145-153.
426. Uhal BD, Rannels SR, Rannels DE. Flow cytometric identification and isolation of hypertrophic type II pneumocytes after partial pneumonectomy. Am J Physiol 1989;257:C528-C536.
427. Uhal BD, Etter MD. Type II pneumocyte hypertrophy without activation of surfactant biosynthesis after partial pneumonectomy. Am J Physiol 1993;264:L153-L159.
428. Waller DA, Keavey P, Woodfine L. Dark JH. Pulmonary endothelial permeability changes after major lung resection. Ann Thorac Surg 1996;61:1435-1440.
429. Lee E, Little AG, Hsu WH, Skinner DB. Effect of pneumonectomy on extravascular lung water in dogs. J Surg Res 1985:38:568-573.
430. Townsley MI, Parker JC, Korthuis RJ, Taylor AE. Alterations in hemodynamics and Kf,c during lung mass resection. J Appl Physiol 1987; 63:2460-2466.
431. Docrschuk CM, Sekhon HS. Pulmonary blood volume and edema in postpneumonectomy lung growth in rats. J Appl Physiol 1990;69: 1178-1182.
432. Diamond J, Hammond K. The matches, achieved by natural selection, between biological capacities and their natural loads. Experientia 1992:48:551-557.
433. Tamhane RM, Johnson RL Jr, Hsia CC. Pulmonary membrane diffusing capacity and capillary blood volume measured during exercise from nitric oxide uptake. Chest 2001;120:1850-1856.
434. Hsia CCW, McBrayer DG, Ramanathan M. Reference values of pulmonary diffusing capacity during exercise by a rebreathing technique. Am J Respir Crit Care Med 1995;152:658-665.
435. Rose GL, Cassidy SS, Johnson RL Jr. Diffusing capacity at different lung volumes during breath holding and rebreathing. J Appl Physiol 1979:47:32-36.
436. Konig MF, Lucocq JM, Weibel ER. Demonstration of pulmonary vascular perfusion by electron and light microscopy. J Appl Physiol 1993: 75:1877-1883.
437. Hanson WL, Emhardt JD, Bartek JP, Latham LP, Checkley LL, Capen RL, Wagner WW. Site of recruitment in the pulmonary microcirculation. J Appl Physiol 1989;66:2079-2083.
438. Hsia CCW, Johnson RL Jr, Shah D. Red cell distribution and the recruitment of pulmonary diffusing capacity. J Appl Physiol 1999;86: 1460-1467.
439. Takeda S, Hsia CCW, Wagner E, Ramanathan M, Estrera AS, Weibel ER. Compensatory alveolar growth normalizes gas exchange function in immature dogs after pneumonectomy. J Appl Physiol 1999;86: 1301-1310.
440. Johnson RL Jr. Heart-lung interactions in the transport of oxygen. In: Scharf S, Cassidy SS, editors. Heart-lung interaction in health and disease. New York: Marcel Dekker; 1989. p. 5-41.
441. Hsia CCW, Carlin JI, Ramanathan M, Cassidy SS, Johnson RL Jr. Estimation of diffusion limitation after pneumonectomy from carbon monoxide diffusing capacity. Respir Physiol 1991;83:11-21.
442. Hsia CCW. Recruitment of lung diffusing capacity: update of concept and application. Chest 2002;122:1774-1783.
443. Hopper JL, Hibbert ME, Macaskill GT, Phelan PD, Landau LI. Longitudinal analysis of lung function growth in healthy children and adolescents. J Appl Physiol 1991:70:770-777.
444. Hibbert M, Lannigan A, Raven J, Landau L, Phelan P. Gender differences in lung growth. Pediatr Pulmonol 1995;19:129-134.
445. Green M, Mead J, Turner JM. Variability of maximum expiratory flowvolume curves. J Appl Physiol 1974;37:67-74.
446. McBride JT. Postpneumonectomy airway growth in the ferret. J Appl Physiol 1985;58:10-1014.
447. Greville HW, Arnup ME, Mink SN, Oppenheimer L, Anthonisen NR. Mechanism of reduced maximum expiratory flow in dogs with compensatory lung growth. J Appl Physiol 1986;60:441-448.
448. Georgopoulos D, Mink SN, Oppenheimer L, Anthonisen NR. How is maximal expiratory flow reduced in canine postpneumonectomy lung growth? J Appl Physiol 1991;71:834-840.
449. Arnup ME, Greville HW, Oppenheimer L, Mink SN, Anthonisen NR. Dynamic lung function in dogs with compensatory lung growth. J Appl Physiol 1984;57:1569-1576.
450. Hsia CCW, Herazo LF, Ramanathan M, Claassen H, Fryder-Doffey F, Hoppeler H, Johnson RL Jr. Cardiopulmonary adaptations to pneumonectomy in dogs: III: ventilatory power requirements and muscle structure. J Appl Physiol 1994;76:2191-2198.
451. Hsia CCW, Peshock RM, Estrera AS, Johnson RL Jr. Work of breathing during exercise in patients after pneumonectomy. Am Rev Respir Dis 1991;143:A347.
452. Hsia CCW, Peshock RM, Estrera AS, McIntire DD, Ramanathan M. Respiratory muscle limitation in patients after pneumoncctomy. Am Rev Respir Dis 1993;147:744-752.
453. Werner HA, Pirie GE, Nadel HR, Fleisher AG, LeBlanc JG. Lung volumes, mechanics, and perfusion after pulmonary resection in infancy. J Thorac Cardiovasc Surg 1993;105:737-742.
454. McBride JT, Wohl ME, Strieder DJ, Jackson AC, Morton JR, Zwerdling RG, Griscom NT, Treves S, Williams AJ, Schuster S. Lung growth and airway function after lobectomy in infancy for congenital lobar emphysema. J Clin Invest 1980;66:962-970.
455. Kirchner KK, McBride JT. Changes in airway length after unilateral pncumonectomy in weanling ferrets. J Appl Physiol 1990;68:187-192.
456. Dane DM, Johnson RL Jr, Hsia CCW. Dysanaptic growth of conducting airways after pneumonectomy assessed by CT scan. J Appl Physiol 2002;93:1235-1242.
457. Hsia CCW, Zhou XS, Bellotto DJ, Hagler HK. Regenerative growth of respiratory bronchioles in dogs. Am J Physiol Lung Cell Mol Physiol 2000;279:L136-L142.
458. Kennedy JD. Lung function outcome in children of premature birth. J Paediatr Child Health 1999;35:516-521.
459. Bhandari A, Bhandari V. Pathogenesis, pathology and pathophysiology of pulmonary sequelae of bronchopulmonary dysplasia in premature infants. Front Biosci 2003;8:e370-e380.
460. Benachi A, Chailley-Heu B, Delezoide AL, Dommergues M, Brunelle F, Dumez Y, Bourbon JR. Lung growth and maturation after tracheal occlusion in diaphragmatic hernia. Am J Respir Crit Care Med 1998;157:921-927.
461. Probyn ME, Wallace MJ, Hooper SB. Effect of increased lung expansion on lung growth and development near midgestation in fetal sheep. Pediatr Res 2000;47:806-812.
462. Harrisen MR, Keller RL, Hawgood SB, Kittcrman JA, Sandberg PL, Farmer DL, Lee H, Filley RA, Farrell JA, Albanese CT. A randomized trial of fetal endoscopie trancheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med 2003;349:1916-1924.
463. Laros CD, Westermann CJJ. Dilatation, compensatory growth, or both after pneumonectomy during childhood and adolescence: a thirty-year follow-up study. J Thorac Cardiovasc Surg 1987;93:570-576.
464. Cagle PT, Thurlbeck WM. Postpneumonectomy compensatory lung growth. Am Rev Respir Dis 1988;138:1314-1326.
465. Giammona ST, Mandelbaum I, Battersby JS, DaIy WJ. The late cardiopulmonary effects of childhood pneumonectomy. Pediatrics 1966;37:79-88.
466. Birath G, Malmberg R, Simonsson BG. Lung function after pneumonectomy in man. Clin Sci 1965;29:59-72.
467. Cournand A, Riley RL, Himmelstein A, Austrian R. Pulmonary circulation and alveolar ventilation-perfusion relationships after pneumonectomy. J Thorac Surg 1950;19:80-116.
468. DeGraff AC Jr, Taylor HF, Ord JW, Chuang TH, Johnson RL Jr. Exercise limitation following extensive pulmonary resection. J Clin Invest 1965;44:1514-1522.
469. Harrison RW, Adams WE, Long ET, Burrows B, Reimann A. The clinical significance of cor pulmonale in the reduction of cardiopulmonary reserve following extensive pulmonary resection. J Thorac Surg 1958;36:352-368.
470. Hijazi OM, Ramanathan M, Estrera AS, Pcshock RM, Hsia CCW. Fixed maximal stroke index in patients after pneumonectomy. Am J Respir Crit Care Med 1998;157:1623-1629.
471. Maeda H, Nakahara K, Ohno K, Kido T, Ikeda M, Kawashima Y. Diaphragm function after pulmonary resection. Am Rev Respir Dis 1988;137:678-681.
472. Van Mieghem W, Demedts M. Cardiopulmonary function after lobectomy or pneumonectomy for pulmonary neoplasm. Respir Med 1989;83:199-206.
473. Haracla K, Hamaguchi N, Shimada Y, Saoyama N, Minamimoto T, Inoue K. Use of sulfur hexafluoride, SF6, in the management of the postpneumoneclomy pleural space. Respiration 1984;46:201-208.
474. Zhou A, Guo L, Tang L. Effect of an intrathoracic injection of sodium hyaluronic acid on the prevention of pleural thickening in excess fluid of tuberculous thoracic cavity. Clin Exp Pharmacol Physiol 2003;30:203-205.
475. Wiseman DM, Trout JR, Franklin RR, Diamond MP. Metaanalysis of the safety and efficacy of an adhesion barrier (Interceed TC7) in laparotomy. J Reprod Med 1999;44:325-331.
476. Peters RM, Roos A, Black H, Burford TH, Graham EA. Respiratory and circulatory studies after pneumonectomy in childhood. J Thorac Surg 1950;20:484-493.
477. Brown LM, Welch DR, Rannels DE, Rannels SR. Partial pneumonectomy enhances melanoma metastasis to mouse lungs. Chest 2002;121:28S-29S.
478. Maniwa Y, Okada M, Ishii N, Kiyooka K. Vascular endothelial growth factor increased by pulmonary surgery accelerates the growth of micrometastases in metastatic lung cancer. Chest 1998;114:1668-1675.
479. Warburton D, Tefft D, Mailleux A, Bellusci S, Thiery JP, Zhao J, Buckley S, Shi W, Driscoll B. Do lung remodeling, repair, and regeneration recapitulate respiratory ontogeny? Am J Respir Crit Care Med 2001;164:S59-S62.
480. Mao JT, Goldin JG, Dermand J, Ibrahim G, Brown MS, Emerick A, McNitt-Gray MF, Gjertson DW, Estrada F, Tashkin DP, et al. A pilot study of all-trans-retinoic acid for the treatment of human emphysema. Am J Respir Crit Care Med 2002;165:718-723.
481. Hirschl RB, Philip WF, Click L, Greenspan J, Smith K, Thompson A, Wilson J, Adzick NS. A prospective, randomized pilot trial of perfluorocarbon-induced lung growth in newborns with congenital diaphragmatic hernia. J Pediatr Surg 2003; 38:283-289; discussion 283-289.
482. Fauza DO, Hirschl RB, Wilson JM. Continuous intrapulmonary distension with perfluorocarbon accelerates lung growth in infants with congenital diaphragmatic hernia: initial experience. J Pediatr Surg 2001;36:1237-1240.
483. Walker GM, Kasem KF, O'Toole SJ, Watt A, Skeoch CH, Davis CF. Early perfluorodecaline lung distension in infants with congenital diaphragmatic hernia. J Pediatr Surg 2003;38:17-20.
484. Latini G, De Felice C, Presta G, Rosati E, Vacca P. Minimal handling and bronchopulmonary dysplasia in extremely low-birth-weight infants. Eur J Pediatr 2003;162:227-229.
485. Kamper J. Early nasal continuous positive airway pressure and minimal handling in the treatment of very-low-birth-weighe infants. Biol Neonate 1999;76:22-28.
486. Coalson JJ, Winter V, deLemos RA. Decreased alveolarization in baboon survivors with bronchopulmonary dysplasia. Am J Respir Crit Care Med 1995;152:640-646.
487. O'Toole SJ, Karamanoukian HL, Irish MS, Sharma A, Holm BA, Click PL. Tracheal ligation: the dark side of in utero congenital diaphragmatic hernia treatment. J Pediatr Surg 1997;32:407-410.
488. Faridy EE, Yang WZ. Role of hyperventilation in hypoxia on lung growth in rats. Respir Physiol 1989;76:179-190.
489. Rannels DE, White DM, Watkins CA. Rapidity of compensatory lung growth following pneumonectomy in adult rats. J Appl Physiol 1979;46:326-333.
490. Hu LM, Davies P, Adzick NS, Harrison MR, Reid LM. The effects of intrauterine pneumonectomy in lambs: a morphomelric study of the remaining lung at term. Am Rev Respir Dis 1987;135:607-612.
491. Sekhon HS, Thurlbeck WM. Lung growth in hypobaric normoxia, normobaric hypoxia, and hypobaric hypoxia in growing rats: I: biochemistry. J Appl Physiol 1995;78:124-131.
492. Massaro GD, Massaro D. Formation of alveoli in rats: postnatal effect of prenatal dexamethasone. Am J Physiol 1992;263:L37-L41. [Published errata appear in Am J Physiol 1992;263(3 Pt 1):frontmatter and 1993;264(2 Pt 1):frontmatter.
493. Plopper CG, St. George JA, Read LC, Nishio SJ, Weir AJ, Edwards L, Tarantal AF, Pinkerton KE, Merritt TA, Whitsett JA, et al. Acceleration of alveolar type II cell differentiation in fetal rhesus monkey lung by administration of EGF. Am J Physiol 1992;262:L313-L321.
494. Morikawa O, Walker TA, Nielsen LD, Pan T, Cook JL, Mason RJ. Effect of adenovector-mediated gene transfer of keratinocyte growth factor on the proliferation of alveolar type II cells in vitro and in vivo. Am J Respir Cell Mol Biol 2000;23:626-635.
495. Fehrenbach H, Fehrenbach A, Pan T, Kasper M, Mason RJ. Keratinocyte growth factor-induced proliferation of rat airway epithelium is restricted to Clara cells in vivo. Eur Respir J 2002;20:1185-1197.
496. Yano T, Mason RJ, Pan T, Deterding RR, Nielsen LD, Shannon JM. KGF regulates pulmonary epithelial proliferation and surfactant pro tein gene expression in adult rat lung. Am J Physiol Lung Cell Mol Physiol 2000;279:L1146-L1158.
497. Deterding RR, Havill AM, Yano T, Middleton SC, Jacoby CR, Shannon JM, Simonet WS, Mason RJ. Prevention of bleomycin-induced lung injury in rats by keratinocyte growth factor. Proc Assoc Am Physicians 1997;109:254-268.
498. Hsia CCW, Johnson RL Jr, Weibel ER. Compensatory lung growth: relationship to postnatal lung growth and adaptation in destructive lung disease. In: Harding R, Pinkerton KE, Plopper CG, editors. The lung: development, ageing and the environment. St. Louis: Elsevier Science; 2004; pp. 187-199.
THIS OFFICIAL WORKSHOP REPORT WAS APPROVED BY THE ATS BOARD OF DIRECTORS DECEMBER 2003.
Members of the ad hoc Statement Committee have disclosed any direct commercial associations (financial relationships or legal obligations) related to the preparation of this statement. This information is kept on file at the ATS headquarters.
This Workshop, held May 18, 2001, in San Francisco, California, was sponsored by the Respiratory Structure and Function Assembly and was co-sponsored by the Respiratory Cell and Molecular Biology Assembly.
CONNIE C.W. HSIA, Chair
Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX.
MARY ANNE BERBERICH
Division of Lung Diseases, National Heart, Lung and Blood Institute, Bethesda, MD.
Children's Hospital Los Angeles Research Institute, University of Southern California, Los Angeles, CA.
VICTOR E. LAUBACH
Thoracic & Cardiovascular Surgery, University of Virginia, Charlottesville, VA.
CRAIG W. LILLEHEI
Department of Surgery, Children's Hospital Harvard Medical School, Boston, MA.
DONALD J. MASSARO
Lung Biology Lab, Georgetown University School of Medicine, Washington, DC.
ELIZABETH A. PERKETT
Pediatric Pulmonary Medicine, University of New Mexico, Albuquerque, NM.
RICHARD A. PIERCE
Department of Medicine, Washington University, St. Louis, MO.
D. EUGENE RANNELS
Cell/Molecular Physiology, Pennsylvania State University, Hershey, PA.
RITA M. RYAN
Division of Neonatology, SUNY Buffalo, Buffalo, NY.
ROBERT S. TEPPER
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN.
MARY I. TOWNSLEY
Department of Physiology, University of South Alabama, Mobile, AL.
KATHLEEN A. VENESS-MEEHAN
Neonatal/Perinatal Medicine, University of North Carolina, Chapel Hill, NC.
Physiology Program, Harvard School of Public Health, Boston, MA.
Children's Hospital Los Angeles Research Institute, University of Southern California, Los Angeles, CA.
Copyright American Thoracic Society Aug 1, 2004
Provided by ProQuest Information and Learning Company. All rights Reserved