Swyer syndrome

The Parker B. Francis Lectureship

(CHEST 2000; 117:282S-285S)

Abbreviations: ALRI = acute lower respiratory tract infection; ICAM = intercellular adhesion molecule; IL = interleukin; RSV = respiratory syncytial virus

Cigarette smoking causes airway and alveolar inflammation in everyone who smokes and is the major risk factor for developing COPD. However, as only 10 to 15% of heavy smokers develop emphysema and airways obstruction,[1] other risk factors must influence cigarette smoke-induced lung inflammation to cause the lesions that produce COPD. Several factors that add risk to cigarette smoking have been identified,[2] but this brief review is designed to concentrate on lower respiratory tract infections with particular reference to the hypothesis that latent adenoviral infection is capable of amplifying cigarette smoke-induced lung inflammation to produce emphysema.

Acute lower respiratory tract infection (ALRI) in childhood is a major worldwide health problem ranked first among conditions contributing to the global burden of disease.[3] Viral infections contribute about 20 to 30% of all cases of ALRI,[4,5] and in a community setting, approximately 53.5% of cases of viral etiology are attributable to respiratory syncytial virus (RSV), 13.9% to adenovirus, 7.0% to influenza, 4.7% to parainfluenza, 2.3% to more than one virus.[4] Studies of pediatric hospital admissions for ALRI, on the other hand, show that the proportion of viral infections fall to 36.3% of all cases with RSV, and adenovirus accounting for the bulk of these admissions.[6]

An important feature of the adenovirus compared to the other common respiratory viruses is that it has a DNA rather than RNA genome. Portions of this viral DNA persist in host cells after viral replication has stopped as either a circular extra chromosome (plasmid) or by integration into the host DNA. This persistence may be important in the pathogenesis of the known sequelae of adenoviral infection that include the Swyer-James syndrome (or unilateral hyperlucent lung), permanent airways obstruction, bronchiectasis, bronchiolitis obliterans, and steroid-resistant asthma.[7-12] Our working hypothesis that this latent adenoviral infection also plays a role in the pathogenesis of COPD, because a protein expressed by the latent viral DNA amplifies the expression of genes that are activated in cigarette smoke-induced airway inflammation.

The adenoviruses are icosahedral particles that are 70 to 100 nm in diameter that consist of a protein shell surrounding a double-stranded DNA core.[13] The genomes of [is greater than] 100 types isolated so far have the same general features, in that they consist of approximately 35 x [10.sup.4] base pairs that contain two origins for DNA replication, five early transcription units, two delayed early units, and one major late unit that is processed to generate five different families of messenger RNA.[14] The replication of the adenovirus is dependent on transcriptional activation that is initiated by activation proteins encoded by one of the early transcription units referred to as the E1A gene.[15,16] During an acute infection, interactions between the adenoviral E1A protein and host transcriptional elements create conditions that are favorable to viral replication. For example, they induce quiescent cells to enter the S phase of the cell cycle and inhibit host cell apoptosis.[14] They also increase the transcription of viral and host genes by interacting with the DNA binding sites of host transcription factors.[14] Early studies using classical hybridization techniques showed that the viral DNA remained in tonsils[16,17] and peripheral blood lymphocytes[18] long after viral replication stopped. Polymerase chain reaction based studies have shown that the adenoviral DNA from the E1A gene is present in human lungs,[19] and immunohistochemistry has shown that E1A protein can be demonstrated in epithelial cells on the surface of conducting airways, epithelial glands, and in type II alveolar cells.[20] The essence of our working hypothesis concerning latent adenoviral infection in emphysema is that the E1A protein in alveolar epithelium amplifies the transcription of host genes expressed during cigarette smoke-induced lung inflammation and increases the migration of inflammatory cells into the alveolar surface.

The opportunity to study lung tissue from a group of children who died of ALRI of proven adenovirus etiology using in situ hybridization showed that the virus targets epithelial cells in both the conducting airways and the gas exchanging surface of the lung where it primarily infected the type II cells.[21] In the normal lung, the type II cells cover approximately 7% of the alveolar surface, produce surfactant, and are the progenitors of the type I cell that cover the remaining 93%.[22] The recognition that inflammatory cells migrate out of vessels and into the alveolar airspace by passing between the type I and type II cells[23] puts the type II cell in an ideal position to influence the inflammatory response in alveolar tissue (Fig 1). Over the past 11 years, we have conducted experiments to determine if the persistence of latent adenoviral infection in lung epithelial cells might amplify cigarette smoke-induced alveolar inflammation.

[Figure 1 ILLUSTRATION OMITTED]

The demonstration of more E1A DNA in lung tissue from patients with COPD than in tissue from age- and gender-matched control subjects with similar smoking histories[19] and the immunohistochemical studies showing that there was E1A protein in airway surface epithelial cells in epithelial glands and in type II cells on the gas exchanging surface of the lung,[22] encouraged us to initiate an in vitro investigation of a type II-like A549 cell.[24,25] The A549 cell line is derived from a peripheral lung carcinoma that has many type II cell characteristics. When these cells are transfected with E1A DNA, they demonstrate lamellar bodies and tight junctions consistent with a type II alveolar cell phenotype,[24] and when challenged with inflammatory stimuli, they produce excess interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1.[29,30] Subsequent studies demonstrated that the presence of E1A protein leads to the activation of nuclear factor [Kappa]B[26] to initiate these changes,[27] and very recent studies have shown that the excess ICAM-1 and IL-8 production induced by tumor necrosis factor-[Alpha] becomes steroid resistant in E1A transfected cells.[28] The observations suggest that latent adenoviral infection of type II cells in situ might provide a mechanism that could amplify cigarette smoke-induced lung inflammation and make it steroid resistant.

When guinea pigs are exposed to cigarette smoke, they develop lung inflammation involving both the conducting airways and gas exchanging surface,[29,30] and chronic exposure produces lesions consistent with human emphysema.[31] When guinea pigs with latent adenoviral infection[32] are exposed to a single dose of cigarette smoke, they develop an excess inflammatory response[33] that could lead to excess emphysema. In a recent collaboration with the University of Pittsburgh, we compared tissue from patients with mild disease obtained by lung resection for tumor to advanced disease obtained from patients undergoing lung volume reduction surgery. Our preliminary findings suggest that there is a greater inflammatory response in the lung in advanced emphysema that is associated with a greater prevalence of E1A protein in the type II alveolar cell.[34] Collectively, these animal and human studies suggest that advanced emphysema is associated with amplification of the cigarette smoke-induced inflammation, and that this excessive response to cigarettes is related to the presence of latent adenoviral infection.

In summary, the cigarette smoking habit is the number-one risk factor for the development of emphysema and chronic airways obstruction, but only 15 to 20% of heavy smokers develop this complication.[1] Lower respiratory tract infection is one of the factors that contribute to the risk of developing COPD, and our studies of latent adenoviral infection suggest mechanisms by which latent adenoviral infection results in amplification of cigarette smoke-induced lung inflammation. Although the studies presented here have focused on adenovirus, the field is open to the possibility that other infectious agents might produce similar results.

REFERENCES

[1] Fletcher C, Peto R, Tinker C, et al. The natural history of chronic bronchitis and emphysema. Oxford, UK: Oxford University Press, 1976

[2] Pride NB, Burrows B. Development of impaired lung function: natural history and risk factors. In: Calverley P, Pride N, eds. Chronic obstructive disease. London, UK: Chapman and Hall Medical, 1995; 69-91

[3] Murray CJL, Lopez AD. Evidence based health policy: lessons from the global burden of disease study. Science 1996; 274:740-743

[4] Avila MM, Carballal G, Rovaletti H, et al. Viral etiology in acute lower respiratory infections in children from a closed community. Am Rev Respir Dis 1989; 140:634-637

[5] Blanding JG, Hoshiko MG, Stutman HR. Routine viral culture for pediatric respiratory specimens submitted for direct immunofluorescence testing. J Clin Microbiol 1989; 27:1438-1440

[6] Videla C, Carballal G, Misirlian A, et al. Acute lower respiratory infections due to respiratory syncytial virus and adenovirus among hospitalized children from Argentina. Clin Diag Virol 1998; 10:17-23

[7] Becroft DM. Bronchiolitis obliterans, bronchiectasis, and other sequelae of adenovirus type 21 infection in young children. J Clin Pathol 1971; 24:72-82

[8] Kollee LA, van Heeswijk PJ, Schretlen ED. Unilateral hyperlucent lung with decreased vascular markings (Swyer-James syndrome). Padiatrie und Padologie 1975; 10:10-18

[9] Simila S, Linna O, Lanning P, et al. Chronic lung damage caused by adenovirus type 7: a ten-year follow-up study. Chest 1981; 80:127-131

[10] Wenman WM, Pagtakhan RD, Reed MH, et al. Adenovirus bronchiolitis in Manitoba: epidemiologic, clinical and radiologic features. Chest 1982; 81:605-609

[11] Sly PD, Soto-Quiros ME, Landau LI, et al. Factors predisposing to abnormal pulmonary function after adenovirus type 7 pneumonia. Arch Dis Child 1984; 59:935-939

[12] Macek V, Sorli J, Kopriva S, et al. Persistent adenoviral infection and chronic airway obstruction in children. Am J Respir Crit Care Med 1994; 150:7-10

[13] Norrby E. The relationship between soluble antigens and the virion of adenovirus type 3; 1. Morphological characteristics. Virology 1966; 28:236-248

[14] Shenk T. Adenoviridae: the viruses and their replication. In: Fields BN, Knipe DM, Howely PM, et al, eds. Fields virology. 3rd ed. Philadelphia, PA: Lippincott-Raven Publishers, 1996; 2111-2148

[15] Shenk T, Flint SJ. Transcriptional and transforming activities of the adenovirus E1A proteins. Adv Cancer Res 1991; 57:47-85

[16] Green M, Wold WSM, Mackey JK, et al. Analysis of human tonsil and cancer DNAs and RNAs for DNA sequences of group C (serotypes 1, 2, 5, and 6) human adenoviruses. Proc Natl Acad Sci USA 1979; 76:6606-6610

[17] Neumann R, Genersch E, Eggers HJ. Detection of adenovirus nucleic acid sequences in human tonsils in the absence of infectious virus. Virus Res 1987; 7:93-97

[18] Horvath J, Palkonyay L, Weber J. Group C adenovirus DNA sequences in human lymphoid cells. J Virol 1986; 59:189-192

[19] Matsuse T, Hayashi S, Kuwano K, et al. Latent adenoviral infection in the pathogenesis of chronic airways obstruction. Am Rev Respir Dis 1992; 146:177-184

[20] Elliott WM, Hayashi S, Hogg JC. Immunodetection of E1A proteins in human lung tissue. Am J Respir Cell Mol Biol 1995; 12:642-648

[21] Hogg JC, Irving WL, Porter H, et al. In situ hybridization studies of lungs and their relationship to follicular bronchiectasis. Am Rev Respir Dis 1989; 139:1531-1535

[22] Crapo JD, Barry BE, Gehr P, et al. Cell number and cell characteristics of the normal human lung. Am Rev Respir Dis 1982; 126:332-337

[23] Walker DC, Behzad AR, Chu F. Neutrophil migration through preexisting holes in the basal lamina of alveolar capillaries and epithelium during streptococcal pneumonia. Microvas Res 1995; 50:397-416

[24] Keicho N, Elliott WM, Hogg JC, et al. Adenovirus E1A gene dysregulates ICAM-1 expression in pulmonary epithelial cells. Am J Respir Cell Mol Biol 1997; 16:23-30

[25] Keicho N, Elliott WM, Hogg JC, et al. Adenovirus E1A upregulates interleukin-8 expression induced by endotoxin in pulmonary epithelial cells. Am J Physiol 1997; 272:L1046-L1052

[26] Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-[Kappa]B. Ann Rev Cell Biol 1994; 10:405-455

[27] Keicho N, Higashimoto Y, Bondy GP, et al. Endotoxin-specific NF-[Kappa]B activation in pulmonary epithelial cells harbouring adenovirus E1A. Am J Physiol 1999; 21:L523-L532

[28] Jamil S, Hayashi S, Hogg JC. Budesonide modulation of adenovirus E1A-mediated inflammation [abstract]. Am J Respir Crit Care Med 1999; 159:A179

[29] Simani AS, Inoue S, Hogg JC. Penetration of the respiratory epithelium of guinea pigs following exposure to cigarette smoke. Lab Invest 1974; 31:75-81

[30] Hulbert CW, Walker DC, Jackson A, et al. Airway permeability of horseradish peroxidase in guinea pigs: the repair phase after injury by cigarette smoke. Am Rev Respir Dis 1981; 123:320-326

[31] Wright JL, Churg A. Cigarette smoke causes physiologic and morphologic changes of emphysema in the guinea pig. Am Rev Respir Dis 1990; 142:1422-1428

[32] Vitalis TV, Keicho N, Itabashi S, et al. An animal model of adenovirus infection. Am J Respir Cell Mol Biol 1996; 14:225-231

[33] Vitalis TZ, Kern I, Croome A, et al. Latent adenovirus 5 infection enhances cigarette smoke induced inflammation. Eur Respir J 1998; 11:664-669

[34] Elliott WM, Coxson HO, Hayashi S, et al. Expression of adenovirus E1A protein with increasing severity of emphysema [abstract]. Eur Respir J 1998; 12(Suppl 28):398

(*) From the University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, Vancouver, British Columbia, Canada.

Correspondence to: James c. Hogg, MD, PhD, University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, 1081 Burrard St, Vancouver, British Columbia, Canada V6Z 1Y6; e-mail: jhogg@prl.pulmonary.ubc.ca

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