Multiple organ failure

At the time of its original description in 1967 by Ashbaugh et al,[1] the adult respiratory distress syndrome (ARDS) was nearly uniformly fatal and was associated with a mortality rate approaching 95 percent. In the past 25 years, much has been learned about the pathophysiology of ARDS.[2-4] These improvements in understanding, coupled with advances in general supportive care (eg, positive end-expiratory pressure ventilation (PEEP), bedside hemodynamic monitoring, and aggressive circulatory support) have led to impressive reductions in the mortality rate associated with ARDS.[5,6] Nonetheless, our understanding of the pathophysiology of ARDS remains incomplete, as evidenced by the fact that ARDS mortality has not changed appreciably in the past decade from its present-day level of 50 percent.

At the present time, progressive, irreversible respiratory failure is an infrequent cause of death in patients with ARDS. Rather, death in patients with ARDS is due, in large part, to the development of multiple organ failure (MOF).[7-16] In this regard, current concepts hold that many of the diverse conditions that place patients at risk for the development of ARDS[2,12] (eg, septic shock, multiple trauma, pancreatitis) result in the generalized intravascular activation of inflammatory cells with resultant endothelial and/or parenchymal injury. This unifying hypothesis of global microcirculatory injury has recently been reviewed[13] and is supported by many clinical studies that have documented organ failure in patients with ARDS.[7-16] Additional support for the concept of global microcirculatory injury in ARDS comes from several studies in animal models of sepsis and/or acute lung injury[14-17] in which significant structural alterations, as well as systemic organ neutrophil accumulation, have been documented in multiple systemic organs. Likewise, a significant alteration in intestinal microvascular permeability has been shown to occur in a model of acute lung injury produced by phorbol myristate acetate, suggesting that there is a functional counterpart to the morphologic abnormalities observed in systemic organs during acute lung injury.[18] Taken together, these studies suggest that activation of inflammatory cells and their mediators plays an important role in the development of widespread organ injury during acute lung injury.

In the past, the treatment of ARDS, septic shock, and MOF has been limited to pharmacologic interventions and supportive care. In this regard, recent clinical trials in which methylprednisolone[19-21] and prostaglandin El[22] have been used in the treatment of ARDS and/or septic shock have been completed and have yielded disappointing results. By contrast, recent advances in cytokine biology and molecular biology have paved the way for innovative immunologic approaches to the treatment of ARDS, septic shock, and MOF (Table 1). Using this approach, specific steps along the inflammatory cascade shown in Figure 1 are targeted for therapy. The results of these studies in both the laboratory and clinical setting have been very encouraging, and form the basis for this review.

ANTIENDOTOXIN ANTIBODIES

Although many clinical disorders are associated with development of ARDS, Gram-negative sepsis has been identified as one of the most common precipitating events.[2,12] Approximately 400,000 cases of the sepsis syndrome occur in the United States each year. However, only 30 percent of these patients are subsequently found to have Gram-negative bacteremia. Whether or not Gram-negative bacteria are recovered in the bloodstream, mortality from the sepsis syndrome remains high (20 to 60 percent).[23,24] This is thought to be due in large part to the biologic effects of endotoxin, which is the lipopolysaccharide component of Gram-negative bacerial cell walls. Specifically, endotoxin stimulates the inflammatory cascade at multiple points and is capable of activating complement, neutrophils, and mononuclear phagocytes.[25-31] In addition, endotoxin is able to cause activated mononuclear cells and neutrophils to release inflammatory mediators[32] and to directly injure endothelial cells.[28,33]

Because of the important role that endotoxin plays in the pathogenesis of septic shock, there has been considerable interest in the evaluation of antibody therapy directed against endotoxin. The goal of immunotherapy in the treatment of serious Gram-negative infections is to prevent or attenuate the adverse effects of endotoxin on the central and systemic vasculature as well as the effects of endotoxin on lung and systemic organ injury. In this context, endotoxin is known to consist of three parts: (1) a species-specific oligosaccharide side chain (O antigen); (2) a core polysaccharide; and (3) a lipid region, known as lipid A, which possesses most of the biologic activity (Fig 2). The core-lipid A portion of endotoxin has a structure and function that are highly conserved among Gram-negative bacterial species; and antibodies generated against Gram-negative mutants, like the J5 strain of Escherichia coli, bind to this portion of the endotoxin molecule.[34] Extensive work has been completed in this area; and numerous studies demonstrate the protective effect of hyperimmune serum directed against core antigens in several animal model of sepsis caused by endotoxin and/or a variety of Gram-negative bacteria.[35-38]

The first clinical study examining the effects of antiendotoxin antibodies on human sepsis was performed by Ziegler et al.[39] In this study, treatment with polyclonal J5 antiserum was shown to reduce mortality by approximately 45 percent in patients with Gram-negative bacteremia. The protective effects of this antiendotoxin antibody were not dependent on whether the patients had septic shock. In addition, the J5 antiserum has been used prophylactically in high-risk surgical patients and has been shown to protect these patients from developing septic shock in the postoperative period.[40] However, it did not affect the incidence of new infections in this group of patients.

Despite promising results with the J5 antiserum, there are several serious drawbacks to the use of a pooled human source of endotoxin antibodies. First, multiple donors are needed because there is no booster response to the J5 mutant. Second, mild toxicity occurs in the vaccinated donors. Third, the effectiveness of the antisera cannot be standardized insofar as antibody content has been shown to vary widely among donors. Finally, there is a risk of transmitting infections (eg, HIV) from the donors to the recipients of the antibody. To circumvent the problems surrounding the use of a pooled human endotoxin antibody in the treatment of septic shock, monoclonal antibodies to endotoxin have been developed.[41] The application of monoclonal antibody technology to endotoxin has permitted large quantities of antiendotoxin antibody to be produced (ie, with specific and consistent biologic activity) without the risk of infectious complications. In addition, since monoclonal antibodies have a long serum half-life, they may also be useful for the prophylactic treatment of high-risk patients.

Experimental studies in animals have confirmed the efficacy of these monoclonal antibodies to endotoxin. For example, in 1985 Teng et al[41] produced a human monoclonal IgM antibody against the lipid A portion of endotoxin which gave significant protection against lethal Gram-negative bacteremia in mice. Feeley and colleagues[42] also demonstrated that the same human monoclonal antibody prevented the endotoxin-induced alterations in lung vascular permeability and increased oxygen radical production in rats. Similarly, murine monoclonal antibodies that cross-react with endotoxin have been developed and have been shown to protect animals from the deleterious consequences of infusions of live Gram-negative bacteria and/or endotoxin.[43-45] However, the utility of these cross-reactive "core" antibodies remains controversial. Several investigators have been unsuccessful in demonstrating protection with these antibodies.[46,47] Furthermore, the data from two recent multicenter clinical trials in which different monoclonal antibodies to endotoxin were used in patients with Gram-negative bacteremia or septic shock are inconclusive and await further study and confirmation.[23,48] [TABULAR DATA OMITTED]

The results and conclusions of the human endotoxin antibody trials are deserving of further comment. Specifically, multicenter, double-blind, randomized, placebo-controlled trials have been performed by Ziegler et al[23] and Greenman et al.[48] In the Ziegler trial, an IgM mouse-human hybrid monoclonal antibody (HA-1A) was used. In the Greenman trial, a murine IgM monoclonal antibody (E5) was used. The HA-1A study demonstrated reduced mortality among patients with Gram-negative bacteremia (with or without shock) who received the antiendotoxin monoclonal antibody, compared with controls (Table 2). Of note, the reductions in mortality from sepsis using HA-1A are very similar to the reductions in mortality achieved with the J5 anti-serum.[39] The E5 study also demonstrated a modest improvement in survival, as well as more frequent resolution of individual organ failures in patients with Gram-negative sepsis. However, these improvements occurred only if shock was not present at the time of entry into the study (Table 2).

The differences between these two studies have been thoroughly reviewed.[49,50] In particular, the HA-1A study used only one dose, while two doses, administered 24 h apart, were given in the E5 study. The definition of shock also differed between the two studies, and the APACHE II scores of patients at the time of entry into the study were substantially higher in the HA-1A trial than in the E5 trial. It is noteworthy that nearly 33 percent of the patients in the treatment groups died despite monoclonal antibody therapy. In addition, survival was not improved for the study populations as a whole in either study (n = 543 in the HA-1A study, n = 486 in the E5 study), despite the fact that all patients met entry criteria and were felt to be good candidates for the antiendotoxin antibody. This suggests that the identification of patients who are likely to benefit this therapy needs to be refined.[51] In addition, the fact that large numbers of patients in these trials did not respond to therapy supports the need to develop additional agents that may interdict the inflammatory cascade at different levels. This is clearly true for the sepsis syndrome and is also likely to apply to many of the clinical conditions that lead to ARDS and MOF.

Additional data regarding the clinical use of the antiendotoxin antibodies has become available since the publication of these initial trials. The second trial using E5 was conducted to examine the benefits of E5 in patients with Gram-negative sepsis (n = 548) who were specifically not in refractory shock.[52] In this study, E5 did not improve survival in patients with documented Gram-negative sepsis (n = 530). However, a trend toward improved survival was noted in a subgroup of 139 patients who developed or presented with evidence of major organ failure. By contrast, an open-label trial of HA-1A in 250 patients the Gram-negative bacteremia and shock demonstrated a 40 percent reduction in expected mortality rates.[53] To date, this finding with HA-1A has been confirmed in a total of 750 patients.

Although specific recommendations for the clinical use of the antiendotoxin antibodies are beyond the scope of this report, this subject recently has been reviewed and debated.[50,54-57] Of note, the Food and Drug Administration has not approved E5 for clinical use and has requested a second, controlled trial of HA-1A. The second HA-1A study will be called the Centocor HA-1A Efficacy in Septic Shock or CHESS, trial, and is scheduled to begin in the summer of 1992.

IMMUNOTHERAPY AND CYTOKINES

The host inflammatory response to an insult (eg, acute lung injury, bacterial infection) is another area of intense investigation. Almost regardless of the underlying insult, the response of the host is to initiate an inflammatory response, with the result that numerous mediators (in particular, the cytokines) are released into the circulation (Fig 1). Work in this area thus far has focused on either antibodies directed against a particular cytokine or antibodies directed against a cytokine receptor. In this section, the results of studies employing antibodies to tumor necrosis factor (TNF) and the interleukin (IL)-1 receptor antagonist will be reviewed.

Tumor Necrosis Factor

Tumor necrosis factor is an important humoral mediator of sepsis and of many of the diverse conditions that lead to ARDS and MOF. In this context, TNF has been shown to reach serum levels 90 min after endotoxin infusion in animals and in healthy human volunteers.[58-61] However, due to its short half-life (14 to 18 min in humans), TNF is rapidly cleared from the systemic circulation and returns to baseline levels within a few hours.[58,62,63] Despite the relatively short half-life of TNF, it is capable of producing a variety of deleterious central and peripheral hemodynamic effects. For example, the infusion of recombinant human TNF into experimental animals and/or humans has been shown to induce a shock-like state that mimics septic shock.[64-67] In addition, TNF infusion causes neutrophils to sequester and adhere to lung capillaries with the result that an ARDS-like pattern of lung edema and hemorrhage develops.[63,66,68] Finally, the intravenous administration of TNF causes widespread systemic organ injury that is characterized by hemorrhage, edema, and inflammatory cell infiltration in numerous systemic organs, including the liver, the kidneys, and the intestines.[32,65,66,68]

Tumor necrosis factor also has numerous effects at the cellular level which may initiate or amplify the inflammatory cascade and, in so doing, add further to the pathogenesis of sepsis, ARDS, and MOF. In this context, TNF is known to stimulate not only the release of several other cytokines (eg, IL-1, IL-6, platelet-activating factor), but also the production of endothelial adhesion molecules, which promote neutrophil-endothelial adherence.[69,70] Likewise, TNF enhances neutrophil phagocytosis and can injure endothelial cells, as manifested by an increase in endothelial cell permeability.[68] However, the strongest evidence supporting the role of TNF in the pathogenesis of septic shock, ARDS, and MOF comes from studies that employ anti-TNF antibodies.[32,64,71,72] Specifically, a significant reduction in mortality was observed in mice that had been passively immunized against TNF and were subsequently given a lethal dose of endotoxin.[72] In addition, monoclonal antibodies to TNF have been shown to reduce mortality and prevent the development of septic shock and MOF in baboons given lethal intravenous doses of live E coli bacteria.[32,71] Finally, anti-TNF antibodies have been shown to provide protection against the development of lethal shock in rabbits given endotoxin.[64]

Despite the favorable effects of TNF antibodies in experimental septic shock, it is noteworthy that their protective effects were restricted to animals that were treated with the antibody prior to the infusion of bacteria or endotoxin. Nonetheless, results from animal studies have been sufficiently encouraging that monoclonal antibodies against TNF have been developed for use in human phase I trials. In this regard, Exley et al[73] have recently reported their results using a murine monoclonal antibody to TNF in the treatment of 14 patients with septic shock. In this phase I study, the investigators noted a significant increase in mean arterial pressure within 24 h of administering the TNF antibody to their septic patients. Moreover, these investigators did not report any adverse reactions to the TNF antibody in doses that ranged from 0.4 to 10.0 mg/kg.[73] Based largely on these preliminary results, a controlled clinical trial of murine anti-TNF antibody in patients with septic shock is currently in progress. However, it remains to be seen whether this treatment will have a clinically beneficial effect in this disorder or in other clinical disorders such as ARDS and MOF.

While TNF monoclonal antibodies could theoretically benefit patients with sepsis due either to Gram-negative or Gram-positive bacteria, several lines of evidence argue against the efficacy of TNF antibodies. First, as noted previously, circulating concentrations of TNF peak early and disappear rapidly after endotoxin challenge in both animals and humans. In this context, the detection of TNF in septic patients has been inconsistent, being found in only 36 percent of patients with septic shock in one study.[74] Second, while high levels of TNF have been found in some illnesses (eg, systemic lupus, malignancy, meningococcemia), its correlation with outcome is variable. Although very high circulating concentrations of TNF have been noted to be a poor prognostic indicator in several studies (ie, they delineate patients with a higher mortality and a higher incidence and severity of ARDS[74-77]), in other studies TNF levels did not predict mortality or the onset of ARDS, shock, disseminated intravascular coagulopathy, or renal failure.[77,78] It is possible that this discrepant observations are due, in part, to the assays used to measure TNF. Nonetheless, most of the experimental evidence suggests that increased TNF levels are unlikely to be specific for, or predictive of, which patients have or will develop sepsis, ARDS, or MOF. At the very least, the levels of TNF that have been reported in the literature appear, in and of themselves, insufficient to cause shock.

A third important factor relates to the timing of administration of TNF antibody. It is clear from experimental studies that timing is critical to therapeutic efficacy. Specifically, in most studies, the TNF antibody had to be given before bacterial or endotoxin challenge in order to be effective.[32,64,72] This requirement has, however, been challenged in a recent study in which protection occurred in primates even when the TNF antibody was given 30 min into a 2-h infusion of a lethal dose of live E coli.[71] Nevertheless, this latter type of response to TNF antibodies appears to be the exception rather than the rule.

Fourth, even when a beneficial effect can be demonstrated, monoclonal antibodies to TNF do not totally abrogate the effects of endotoxin, an observation that undoubtedly reflects the importance of other mediators in the pathogenesis of these complex disorders (Fig 1). In this context, Gram-negative bacteremia in baboons induces a sharp rise in circulating levels of IL-1 and IL-6, which are attenuated, but not eliminated, by pretreatment with TNF antibody.[79] Finally, monoclonal antibodies to TNF may not be effective against all pathogens or even against all Gram-negative organisms. For example, mortality due to fungal sepsis appears to occur by a TNF-independent mechanism.[80] Likewise, although antibodies to TNF have been shown to increase survival in mice after E coli challenge, only transient benefits were noted in animals challenged with Pseudomanas aeruginosa, and no benefits were seen in animals challenged with Klebsiella pneumoniae.[81] Based on these observations, it is clear that for TNF antibodies to be effective, the antibody must be given before, or very soon after, the onset of the bacterial infection. In addition, in view of its widely varying efficacy against specific pathogens, TNF antibodies are not likely to be beneficial in all or even most patients with septic shock. These issues, however, promise to be definitively resolved by the ongoing clinical trial of TNF antibody in patients with sepsis.

IL-1 and IL-1 Receptor Antagonist

The polypeptide hormone IL-1 is another important factor in host defense and, like TNF, is an important mediator of disease. Interleukin-1 exists in two forms, IL-1[alpha] and IL-1[Beta]. Both are potent proinflammatory monokines with biologic effects that include fever, endothelial cell activation, increased adhesion molecule receptor expression, hypotension, and shock.[82-84] In addition, IL-1 promotes the release of other cytokines (eg, TNF, IL-6, and platelet activating factor) and acts synergistically with TNF in the production of many of its biologic and inflammatory effects.[84] Like TNF, serum levels of IL-1 rise after endotoxin infusion.[61] However, in contrast to TNF, serum levels of IL-1 reach their peak 3 to 4 h after endotoxin challenge.[84] Finally, infusion of IL-1 into experimental animals induces a shock-like state that is characterized by hypotension, endothelial cell injury, increased vascular permeability, and death.[85]

While murine antibodies capable of neutralizing the effects of IL-1 have been produced and may be useful, in vivo studies utilizing this antibody have not been reported. Rather, attention has focused on the recombinant IL-1 receptor antagonist (IL-1ra).[44,86-89] This naturally occurring protein is the third member of the IL-1 family, and it has been shown to bind to the IL-1 receptor with an avidity that is approximately equal to that of IL-1[alpha] and IL-1[beta].[88] In its recombinant form, the IL-1 receptor antagonist blocks the effects of IL-1 (both in vitro and in vivo) but possesses no agonist activity.[88-90] Significant quantities of endogenous IL-1ra are produced in healthy human volunteers following endotoxin challenge.[86,87] In fact, in the setting of endotoxin challenge, levels of endogenous IL-1ra are 100-fold higher than IL-1 levels, peaking 1 to 2 h after maximal levels of IL-1 are achieved. Taken together, these observations suggest that IL-1ra may be a potent in vivo regulator of the host defense response in both health and disease.

Additional support for the potential importance of this mediator in disorders of host defense may be derived from a number of elegant animal studies. In particular, data from animals suggests that IL-1ra is capable of significantly improving survival and attenuating the hemodynamic, metabolic, and hematologic derangements that occur after live E coli infusion- or endotoxin-induced shock.[91,92] Moreover, IL-1ra reduces neutrophil emigration and infiltration into the lungs in response to live E coli infusion and/or the intratracheal administration of endotoxin or IL-1.[93] Perhaps most significantly, IL-1ra reduces mortality from endotoxin-induced shock in rabbits, even when it is administered after endotoxin challenge.[92,94]

It appears clear that IL-1ra attenuates many of the biologic effects of IL-1, including hypotension, leukopenia, neutrophil activation, shock, and death. However, studies to date have demonstrated that a large excess of IL-1ra is needed to achieve biologic efficacy.[86,95] This may be due, in part, to the sensitivity of the IL-1 receptor complex to IL-1 and/or its relative insensitivity to IL-1ra. Nonetheless, the potential advantages of a receptor antagonist over the monoclonal antibodies are numerous and include the fact that transfusion-related complications can be avoided and the fact that large-scale production can be achieved with greater ease. Furthermore, the lower molecular weight of receptor antagonists may allow them to gain easier access to extravascular sites in tissue.

In keeping with these theoretical advantages, a promising clinical trial by Gordon et al[96] demonstrated that IL-1ra was effective in reducing 28-day mortality (from all causes) in patients with the sepsis syndrome. In addition, the survival rate in this study was shown to be dose-dependent, with an 84 percent survival rate in patients who received the highest dose of IL-1ra (133 mg/h for 72 h). Finally, these investigators demonstrated that both the total lenght of hospital stay and the total length of ICU stay were reduced in patients treated with IL-1ra.[96] The results of further clinical trials are eagerly awaited.

OTHER MEDIATORS AND POTENTIAL TREATMENTS FOR SEPTIC SHOCK

There has been a virtual explosion in the number of locations along the inflammatory cascade that are potential sites for modulation using monoclonal antibodies and/or receptor antagonists. Although work in this area has centered primarily on IL-1ra and on antibodies to endotoxin and TNF, it is clear that numerous other potential treatments loom on the horizon. These treatment options will now be reviewed and include, among others, antibodies to IL-6, IL-8, tissue factor, bactericidal permeability-increasing protein (BPI), and leukocyte adhesion molecules.

Interleukin-8

Interleukin-8 is a recently described peptide that is secreted by a variety of cells (ie, alveolar macrophages, monocytes, endothelial cells) in response to stimulation by endotoxin, TNF, or IL-1.[97] Interleukin-8 causes chemoattraction and activation of neutrophils in vitro and is believed to mediate tissue neutrophil recruitment in host defense and disease.[98,99] Although its precise role in host defense remains to be fully elucidated, it has been found in increased concentrations in primates after IL-1 infusion and after lethal E coli infusion and/or sublethal endotoxin challenges.[100] In addition, IL-8 has been detected in the serum of patients with septic shock,[101] in the serum of normal human volunteers following endotoxin infusion,[102] and in bronchoalveolar lavage fluid or pulmonary edema fluid from patients with ARDS.[103-105] Taken together, these observations suggest that IL-8 may play an important role in the pathogenesis of sepsis and/or ARDS and thus may be an important target for immunotherapy in these disorders.

One potentially confounding feature of IL-8 relates to the fact that its effects are not confined to its proinflammatory functions. Rather, both endothelial-derived IL-8 and recombinant IL-8 have been shown to inhibit neutrophil adherence to IL-1-activated endothelial cells. In this regard, IL-8 may play a protective role in host defense by limiting inflammatory cell-induced tissue injury.[106] To further confuse the issue, Detmers et al[107] and Carveth et al[108] demonstrated that IL-8 enhances the binding affinity of adhesion molecules on human neutrophils. Thus, the exact function of IL-8 on neutrophil-endothelial cell adherence (ie, proinflammatory vs anti-inflammatory) remains unclear. In any case, inhibition of IL-8 with monoclonal antibodies could attenuate lung and/or systemic organ injury by reducing neutrophil activation and chemoattraction. However, it remains to be determined whether IL-8 inhibition by monoclonal antibodies will be beneficial in patients with sepsis, ARDS, or MOF.

Interleukin-6

Interleukin-6 is another cytokine in the inflammatory network that plays an intergral role in host defense. Expression of IL-6 is induced in many cells, including mononuclear phagocytes and endothelial cells, after stimulation by endotoxin, IL-1, or TNF.[109] In addition to numerous other functions, IL-6 is thought to promote neutrophil activation and accumulation at sites of inflammation.[109] In keeping with these properties of IL-6, increased plasma concentrations of IL-6 have been detected in patients with sepsis[110] and are associated with increased mortality in patients with meningococcemia or Gram-negative septic shock.[110,111] Elevated IL-6 levels have also been detected in humans after endotoxin or TNF infusion.[112,113] Finally, the elevated IL-6 levels induced by lethal Gram-negative bacteremia in baboons are attenuated by monoclonal antibodies to TNF.[79]

In an attempt to block the effects of IL-6 and thus potentially define a role for the modification of IL-6 in specific disease states, both a murine IL-6 monoclonal antibody and a murine IL-6 receptor antibody have been developed and tested in animals.[114-116] With respect to the murine IL-6 monoclonal antibody, Starnes et al[114] have shown that this antibody protects mice from the lethal effects of both TNF infusions and E coli infusions. Furthermore, these investigators have shown that antibodies to TNF reduce IL-6 levels after E coli infusion suggesting that TNF plays a regulatory role in IL-6 production.[114] Finally, the fact that mice challenged with E coli in the presence of the IL-6 monoclonal antibody had increased serum TNF bioactivity suggests that IL-6 may serve to down-regulate TNF production/release in vivo.[114]

The results of studies utilizing the soluble IL-6 receptor differ considerably from those described for the IL-6 monoclonal antibody. Specifically, in contrast to the expected anti-inflammatory effect, the soluble IL-6 receptor was found to enhance IL-6 production and increase its inflammatory effects.[115] Although it is premature to draw conclusions from this information regarding the utility of inhibiting IL-6 activity with either monoclonal antibodies or soluble receptor complexes in the management of ARDS, sepsis, or MOF, it does serve to illustrate the highly complex balance that exists between host defense and disease. In addition, these data suggest that immunotherapy must be applied with caution to human disease.

Bactericidal Permeability-Increasing Protein

Bactericidal permeability-increasing protein is a novel protein derived from neutrophil granules that binds to endotoxin.[117] It has the ability to kill bacteria in vitro by increasing the permeability of bacterial cell walls, an effect that is blocked in vivo by plasma proteins.[118] Although much remains to be elucidated about this protein, endogenously produced BPI appears to bind to endotoxin and neutralize its effects via the prevention of macrophage activation.[117] The potential clinical utility of BPI in septic shock is evidenced by the fact that BPI infusions are known to significantly improve survival following lethal E coli bacteremia in rats.[115] Based largely on these findings, phase I trials are scheduled to begin in the near future. However, this protein may have limitations that are similar to those of the antiendotoxin antibodies. Namely, this protein may be efficacious for Gram-negative infections only.

Tissue Factor

The fact that activation of the clotting cascade may play an important role in the pathogenesis of ARDS and sepsis is well documented.[8] However, the role, if any, of tissue factor in this and other disorders has only recently been described. Tissue factor is a potent activator of the coagulation cascade that is produced by monocytes, macrophages, and endothelial cells in response to stimulation with endotoxin[119] (Fig 1). Moreover, tissue factor is released by endothelial cells in response to stimulation with TNF and IL-1.[119]

In support of altered coagulation in the pathogenesis of sepsis, Taylor et al[120] have shown that the infusion of protein C into baboons protects them from the lethal effects of E coli bacteremia. Since tissue factor is such a potent activator of coagulation, these findings suggest a possible in vivo role for tissue factor in the pathogenesis of sepsis. In keeping with this postulate, Taylor et al[119] were able to reduce mortality and block coagulopathy in E coli-infected baboons that received an antibody to tissue factor. The implications of this study are important and suggest that antibodies to tissue factor may add yet another tool for interdicting the events that lead to sepsis, ARDS, and MOF.

LEUKOCYTE ADHERENCE ANTIBODIES

The accumulation of activated neutrophils in the lungs and other organs is felt to play a key role in the pathogenesis of ARDS[3,4,121,122] and MOF.[17] However, the precise sequence of events that leads to neutrophil accumulation in the lungs and systemic organs in these disorders remains unclear. Despite these uncertainties, the central role of inflammatory cells in the pathogenesis of lung and systemic organ injury is clear and is supported by several lines of evidence. First, there is a striking influx of neutrophils and their products (eg, collagenase, myeloperoxidase) into bronchoalveolar lavage fluid from ARDS patients.[121,123-125] Second, alveolar macrophages are known to become activated during endotoxemia and to produce chemotactic factors for neutrophils.[126] These chemotactic factors account, in part, for neutrophil accumulation in the lungs during sepsis. Moreover, once these neutrophils gain access to the lungs, they are capable of producing both epithelial and endothelial injury via the release of proteases and reactive oxygen species.[122,127] Finally, in animal models of acute lung injury produced by endotoxin, live bacteria, intratracheal hydrochloric acid, or intravenous phorbol myristate acetate, there is widespread neutrophil accumulation in systemic organs and morphologic/permeability alterations consistent with systemic organ injury.[14-18,128] Taken together, these observations argue strongly that the neutrophil is an important effector cell in the pathogenesis of both the lung and the systemic organ injury that occurs during conditions that lead to acute lung injury.

An important first step in the process of neutrophil-mediated organ injury involves the binding of neutrophils to endothelial cells.[70,129] Although nonspecific binding between these cells can occur, this interaction is largely regulated by complementary adherence molecules that are present on these cells and that are expressed in increasing numbers in response to a wide variety of stimuli (eg, endotoxin, TNF, endotoxin, IL-1, IL-8).[70,107,108] Several different adherence molecules have been described.[130,131] However, the CD11-CD18 adherence complex, which is present on macrophages and neutrophils, is particularly important and mediates leukocyte adherence to endothelial cells.[130,131]

Monoclonal antibodies directed against the CD18 portion of the leukocyte adherence complex have been developed and have been shown to block CD18-dependent neutrophil-endothelial adherence both in vivo and in vitro. The neutrophil-endothelial cell adherence that is induced in vitro by endotoxin, IL-1, and TNF can be blocked by an anti-CD18 monoclonal antibody.[132] However, the utility of these CD18 receptor antibodies is not restricted to in vitro systems. For example, in animal models of ischemia-reperfusion injury (a process that is neutrophil-mediated), CD18 monoclonal antibodies have been shown to block lung,[133] myocardial,[134] and ileal[135] injury, respectively. Likewise, pretreatment with a CD18 monoclonal antibody is able to block neutrophil sequestration and acute lung injury induced by phorbol myristate acetate in isolated rat lungs.[136] In addition, multiple organ injury is markedly attenuated in rabbits[137] and primates[138] that receive a CD18 monoclonal antibody during hemorrhagic shock. Similarly, the increased levels of TNF and CD18 expression that occur in pigs following live P aeruginosa infusion and that result in neutropenia and increases in bronchoalveolar lavage fluid protein, can be blocked by a CD18 monoclonal antibody.[139,140] Finally, CD18 monoclonal antibodies have been shown to block the permeability changes and morphologic changes that occur in the intestines of cats after acute lung injury that is induced by intratracheal hydrochloric acid.[128] Taken together, these observations strongly support the concept that inhibiting the ability of inflammatory cells to adhere to endothelial cells via CD18 monoclonal antibodies may attenuate tissue injury in several disorders. However, for unclear reasons, these antibodies do not have a consistently beneficial effect on the development of lung and/or systemic organ injury during sepsis.[141,142]

Clinical trials employing these potentially beneficial antibodies are currently being planned. However, there are practical considerations that may limit their widespread use in clinical settings. Specifically, concern exists that these antibodies may increase susceptibility to bacterial infections by interfering with normal host defense. Sharar et al[143] demonstrated that the frequency and severity of subcutaneous abscess formation was increased after Staphylococcus aureus injections in rabbits that were treated with CD18 monoclonal antibodies. This was presumably due to delayed leukocyte migration into the inoculated tissue. However, the clinical significance of these findings remains to be determined since exposure to the quantity of bacteria employed in this study rarely occurs in patients.

SUMMARY

Advances in cytokine biology and molecular biology have led to the development of novel immunologic approaches to the treatment of septic shock, ARDS, and MOF. These advances are necessary since improvements in supportive care clearly fall short of the hoped-for reductions in mortality associated with these disorders. As noted in this review, these new therapies are directed at three distinct levels of the inflammatory cascade: (1) the inciting event or insult (eg, endotoxin); (2) the mediators (eg, TNF, IL-1); and (3) the effector cells (eg, neutrophils). The current status of these treatments has been reviewed; and while each individual therapy has shown potential, it is likely that combinations of these agents may be necessary to substantially impact on survival. That is, due to the complexity and redundancy of the inflammatory network, it is doubtful that a "magic bullet" will be found. However, it is also clear that advances in our understanding of the pathogenesis of ARDS, septic shock, and MOF at the molecular level have provided clinicians with powerful weapons with which to do battle. It remains to be seen which ones will work the best.

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