Immunologic Therapy for ARDS, Septic Shock, and Multiple-Organ Failure

clinical implications of basic research Immunologic Therapy for ARDS, septic Shock, and Multiple-organ Failure* Roy C. St. John, M.p.; and Paul M. Dorinsky, M.D.

(Chest 1993; 103:932-43)

=

BPI bactericidal permeability-increasing protein; IL

=inter-

1euIcin; IL-lra= recombinant IL-l receptor antagonist; MOF= multiple organ failure; TNF=tumor necrosis factor

..lt the time of its original description in 1967 by 1"1. Ashbaugh et ai, I 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 ARDS2.12 (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 *From the Department of Medicine, Division of Pulmonary and Critical Care Medicine, Ohio State University, Columbus. Reprint requests: Dr. St. John, N325 Means HaU, 1654 Upham Drive, Columbus, Ohio 43210

932

injury'4"7 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 '" 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 M0 F has been limited to pharmacologic interventions and supportive care. In this regard, recent clinical trials in which methylprednisolone'":" and prostaglandin EI22have 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 I). 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 bacterial cell walls. Specifically, Immunologic Therapy lor ARDS (St. John,DorinsJcy)

Table I-Immunologic Therapyfor ARDS, Sepsis, andMO?

Site of Action

Animal Studies

HA-IA

LPS

Efficacious

E5

LPS

Efficacious

BPI TNF MoAb IL-Ira IL-8 MoAb IL-6MoAb MoAb 60.3

TFMoAb

LPS TNF IL-I receptor IL-8 IL-6 CD WCD 18

TF

Efficacious Efficacious Efficacious Pending Preliminary Hemorrhagic shock completed (ARDS and MOF ongoing) Preliminary

Status of Clinical Trials Completed, FDA release pending Completed, FDA approval pending Pending Phase III Phase WIll Phase I

The first clinical study exammmg 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 Gramnegative bacteremia. The protective effects of this antiendotoxin antibody were not dependent on whether the patients had septic shock. In addition, the }5 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." 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

*LPS = lipopolysaccharide; FDA = Food and Drug Administration; BPI = bactericidal permeability-increasing protein; TNF = tumor necrosis factor; IL-Ira=interleukin-I receptor antagonist; TF = tissue factor; MoAb = monoclonal antibody.

endotoxin stimulates the inflammatory cascade at multiple points and is capable of activating complement, neutrophils, and mononuclear phagocytes.P?' In addition, endotoxin is able to cause activated mononuclear cells and neutrophils to release inflammatory mediators" 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 (0 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 }5 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 models of sepsis caused by endotoxin and/or a variety of Gram-negative bacteria.:J5.3H

Release Of Monoklnes, Proteases, Oxidants, Arachadonoid Metabolites, Kin_sAnd Tissue Fador

FIGURE 1. Proposed scheme for the pathogenesis of global microcirculatory failure. Following an initial insult (eg, bacterial infection), complement, in8ammatory cells, and endothelial cells become activated. In response to these events, a host of in8ammatory mediators (eg, monokines, proteases, oxidants, arachadonoid metabolites, kinases, tissue factor) are released. The activation of the in8ammatory cells and endothelial cells, coupled with the release of in8ammatory mediators, leads to increased in8ammatory cellendothelial cell adherence, intravascular coagulation, and local tissue injury. The ultimate result of these interrelated events is circulatory collapse and multiple organ injury. CHEST I 103 I 3 I MARCH. 1993

933

FIGURE

2. Generalized structure of endotoxin.

o Antigen-oligosaccharide antigen side chain. 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." 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" 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" 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. 23.46 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 al23 and Greenman et al. 46 In the Ziegler trial, an IgM mouse-human hybrid monoclonal antibody (HA-IA) was used. In the Greenman trial, a murine IgM monoclonal antibody (E5) was used. The HA-IA 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-IA are very similar to the reductions in mortality achieved with the J5 anti-serum.P' 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-

Table 2-30-DtIy MortaUty Ratafor AntimtlotoDn Antibodiea HA-lA and ES.

HA-lA All patients (n = 543) Patients with GNB All (n= 197) Shock (n = 101) E5 All patients (n = 468) Patients with GNI and sepsis (n = 316) Shock (n = 179) No shock (n = 137) Bacteremic Nonbacteremic

Agent

Placebo

39%

43%

30% 33%

49% 57%

40% 38% 45% 30% 27% 33%

41% 41% 40% 43% 37% 46%

Reduction

p Value NS

39% 42%

0.014 0.017 NS NS NS

0.03 NS NS

*GNB = Gram-negative bacteremia; NS = not slgmflcant: GN! = Gram-negative infection.

934

Immunologic Therapy lor ARDS (St. John, Dorinsky)

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." 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 = 847) 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 Gramnegative 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)-l receptor antagonist will be reviewed. Tumor Necrosis Bactor

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. ~1 However, due to its short halflife (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. 6U7 In addition, TNF infusion causes neutrophils to sequester and adhere to lung capillaries with the result that an ARDS-like pattern oflung 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 •7o Likewise, TNF enhances neutrophil phagocytosis and can injure endothelial cells, as manifested by an increase in endothelial cell permeability'" 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.32.54.71.72 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.P 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 baeteria. 32.71 Finally, anti-TNF antibodies have been shown to provide protection against the development oflethal shock in rabbits given endotoxin.54 CHEST I 103 I 3 I MARCH. 1993

935

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 al73 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." 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 Gramnegative or Gram-positive bacteria, several lines of evidence argue against the efficacy ofTNF 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 ARDS74-77), 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 these 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 TN F 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 936

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 oflive E coli." 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 I). In this context, Gram-negative bacteremia in baboons induces a sharp rise in circulating levels of IL-I 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.s" 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 Pseudomonas 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 ofTNF antibody in patients with sepsis. IL-I and IL-I Receptor Antagonist

The polypeptide hormone IL-I is another important factor in host defense and, like TNF, is an important mediator of disease. Interleukin-I exists in two forms, IL-Ia and IL-II3. Both are potent proin8ammatory monokines with biologic effects that include fever, endothelial cell activation, increased adhesion molecule receptor expression, hypotension, and shock. 82-84 In addition, IL-I 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 in8ammatory effects. 84 Like TNF, serum levels of IL-I rise after endotoxin infusion." However, in contrast to TNF, serum levels of IL-I reach their peak 3 to 4 h after endotoxin challenge." Finally, infusion ofIL-I into experimental animals induces a shock-like state that is characterized by hypotension, endothelial cell injury, increased vascular permeability, and death. 85 Immunologic Therapy lor ARDS (Sf. John, Dorinsky)

While murine antibodies capable of neutralizing the effects ofIL-I 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-I receptor antagonist (IL-lra).44.86-89 This naturally occurring protein is the third member of the IL-I family, and it has been shown to bind to the ILl receptor with an avidity that is approximately equal to that ofIL-ia and IL-IJ3.88 In its recombinant form, the IL-I receptor antagonist blocks the effects ofIL-I (both in vitro and in vivo) but possesses no agonist activity.88-1lO Significant quantities of endogenous ILIra are produced in healthy human volunteers following endotoxin challenge.v-" In fact, in the setting of endotoxin challenge, levels of endogenous IL-lra are lOO-fold higher than IL-I levels, peaking 1 to 2 h after maximal levels of IL-I are achieved. Taken together, these observations suggest that IL-Ira 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-Ira 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. 9 1•92 Moreover, IL-lra reduces neutrophil emigration and infiltration into the lungs in response to live E coli infusion and/or the intratracheal administration of endotoxin or IL-l. 93 Perhaps most significantly, IL-lra reduces mortality from endotoxin-induced shock in rabbits, even when it is administered after endotoxin challenge. 92 •94 It appears clear that IL-Ira attenuates many of the biologic effects of IL-I, including hypotension, leukopenia, neutrophil activation, shock, and death. However, studies to date have demonstrated that a large excess of IL-Ira is needed to achieve biologic efficacy.Il6·95 This may be due, in part, to the sensitivity of the IL-I receptor complex to IL-I and/or its relative insensitivity to IL-lra. 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 al95 demonstrated that IL-Ira 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-

Ira (133 mg/h for 72 h). Finally, these investigators demonstrated that both the total length of hospital stay and the total length ofICU stay were reduced in patients treated with IL-Ira. 96 The results of further clinical trials are eagerly awaited. OrHER MEDIATORS AND POTENTIAL TREATMENTS FOR SEPTIC SHOCK

There has been a virtual explosion in the number of locations along the inBammatory cascade that are potential sites for modulation using monoclonal antibodies and/or receptor antagonists. Although work in this area has centered primarily on IL-lra 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-l. fIT 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-l 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,'?' in the serum of normal human volunteers following endotoxin infusion,'02 and in bronchoalveolar lavage Buid or pulmonary edema Buid from patients with ARDS.HI3-I05 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 proinBammatory functions. Rather, both endothelialderived IL-8 and recombinant IL-8 have been shown to inhibit neutrophil adherence to IL-l-activated endothelial cells. In this regard, IL-8 may playa protective role in host defense by limiting inBammatory cellinduced 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, proinBammatory vs anti-inBammatory) remains unclear. In any case, inhibition of IL-8 with monoclonal antibodies could attenuate lung and/or CHEST I 103 I 3 I MARCH. 1993

937

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 integral role in host defense. Expression ofIL-6 is induced in many cells, including mononuclear phagocytes and endothelial cells, after stimulation by endotoxin, IL-I, or TNF.I09 In addition to numerous other functions, IL-6 is thought to promote neutrophil activation and accumulation at sites of Inflammation.'?" In keeping with these properties of IL-6, increased plasma concentrations of IL-6 have been detected in patients with sepsis't? 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 Gramnegative bacteremia in baboons are attenuated by monoclonal antibodies to TN F.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-6levels after E coli infusion suggestng that TNF plays a regulatory role in IL-6 production.t'" 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 938

novel protein derived from neutrophil granules that binds to endotoxin.t'? It has the ability to kill bacteria in vitro by increasing the permeability ofbacterial cell walls, an effect that is blocked in vivo by plasma proteins.!" 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.t'" 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 Gramnegativeinfectionsonl~

TISsue Iactor

The fact that activation of the clotting cascade may play an important role in the pathogenesis of ARDS and sepsis is well documented." 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!" (Fig I). 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 l 20 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 ofcoagulation, 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 M 0 F. LEUKOCYTE ADHERENCE ANTIBODIES

The accumulation of activated neutrophils in the lungs and other organs is felt to playa key role in the pathogenesis of ARDS3.4.121.122 and MOF 17 However: the precise sequence of events that leads ~o neutrophU accumulation in the lungs and systemic organs in these disorders remains unclear. Despite these uncertainties, the central role of inflammatory cells in the pathogenesis oflung 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 InvnunologlcTherapy lor ARDS (Sf. John.Dorlnsky)

Second, alveolar macrophages are known to become activated during endotoxemia and to produce chemotactic factors for neutrophils.P" 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. I22,I27 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.14-18.126 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 neutrophilmediated organ injury involves the binding of neutrophils to endothelial cells. 7o,l29 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, ILl, IL_8).70,107,108 Several different adherence molecules have been described.P'-"! However, the COII-COI8 adherence complex, which is present on macrophages and neutrophils, is particularly important and mediates leukocyte adherence to endothelial cells.I30.131 Monoclonal antibodies directed against the C018 portion of the leukocyte adherence complex have been developed and have been shown to block COI8dependent neutrophil-endothelial adherence both in vivo and in vitro. The neutrophil-endothelial cell adherence that is induced in vitro by endotoxin, IL-l, and TNF can be blocked by an anti-COl8 monoclonal antibody.132 However, the utility of these C018 receptor antibodies is not restricted to in vitro systems. For example, in animal models of ischemia-reperfusion injury (a process that is neutrophil-mediated), C018 monoclonal antibodies have been shown to block lung,l33 myocardial.P' and ileal l35 injury, respectively. Likewise, pretreatment with a C018 monoclonal antibody is able to block neutrophil sequestration and acute lung injury induced by phorbol myristate acetate in isolated rat lungs.P' In addition, multiple organ injury is markedly attenuated in rabbits':" and primates'P" that receive a CO18 monoclonal antibody during hemorrhagic shock. Similarly, the increased levels ofTNF and C018 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 C018 monoclonal

antibody.139,140 Finally, CO18 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 .126 Taken together, these observations strongly support the concept that inhibiting the ability of inflammatory cells to adhere to endothelial cells via C018 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 l43 demonstrated that the frequency and severity of subcutaneous abscess formation was increased after Staphylococcus aureus injections in rabbits that were treated with C018 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, AROS, 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-l); 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 necesssary 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 AROS, 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. REFERENCES

1 Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute CHEST I 103 I 3 I MARCH, 1993

939

respiratory distress in adults. Lancet 1967; 2:319-23 2 Fowler AA, Hamman RF, Good [T, Benson KN, Baird M, Eberle DJ, et al. Adult respiratory distress syndrome: risk with common predispositions. Ann Intern Med 1983; 99:293-98 3 Rinaldo JE, Rogers RE. Adult respiratory distress syndrome: changing concepts of lung injury and repair. N Engl J Med 1982; 306:900-19 4 Tate RM, Repine JE. Neutrophils and the adult respiratory distress syndrome. Am Rev Respir Dis 1983; 128:552-59 5 Fowler AA, Hamman RF, Zerbe GO, Benson KN, Hyers TM. Adult respiratory distress syndrome. Am Rev Respir Dis 1985; 132:472-78 6 Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985; 132:485-89 7 Bell RC, Coalson JJ, Smith JD, Johanson WR. Multiple organ system failure and infection in the adult respiratory distress syndrome. Ann Intern Med 1983; 99:293-98 8 Bone RC, Francis PB, Pierce AK. Intravascular coagulation associated with the adult respiratory distress syndrome. Am J Med 1976; 61:585-89 9 Carrico CJ, Meakins JL, Marshall JC, Fry D, Maier RY. Multiple-organ failure syndrome. Arch Surg 1986; 121:196-208 10 Dorinsky PM, Gadek JE. Mechanisms of multiple nonpulrnonary organ failure in ARDS. Chest 1989; 96:885-92 11 Eiseman B, Beart R, Norton L. Multiple organ failure. Surg GynecolObstet 1977; 144:326 12 Pepe PE, Potkin RT, Reus DH, Hudson LD, Carrico CJ. Clinical predictors of the adult respiratory distress syndrome. Am J Surg 1982; 144:124-30 13 Dorinsky PM, Gadek JE. Multiple organ failure. Clin Chest Med 1990; 581-92 14 Coalson JJ, Archer LT, Benjamin BA, Bellertodd BK, Hinshaw LB. A morphologic study of live Escherichia coli organism shock in baboons. Exp Mol Patho11979; 31:10-22 15 Coalson JJ, Archer LT, Benjamin BA, Beller-Todd BK, Hinshaw LB. Pathophysiologic responses of the subhuman primate in experimental septic shock. Lab Invest 1975; 32:561-69 16 Natanson C, Cunnion RE, Barrett DA, Peart KW, Danner RL, Conklin JJ, et al. Reversible myocardial dysfunction in a canine model of septic shock is associated with myocardial microcirculatory damage and focal neutrophil infiltration. Clin Res 1986; 34:639A 17 Mizer L, Weisbrode S, Dorinsky PM. Neutrophil accumulation and structural changes in nonpulmonary organs following phorbol-myristate-acetate-induced acute lung injury. Am Rev Respir Dis 1989; 139:1017-26 18 St. John RC, Mizer LA, Weisbrode SE, Dorinsky PM. Increased intestinal protein permeability in a model of lung injury induced by phorbol myristate acetate. Am Rev Respir Dis 1991; 144:1171-76 19 Bone RC, Fisher CJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA, et al. A controlled clinical trial of high-dcse methylprednisolone in the treatment of severe sepsis and septic shock. N En~l J Med 1987; 317:653-58 20 Bernard GR, Luce JM, Sprung CL, Rinaldo JE, Thte RM, Sibbald WJ, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N EnIP J Med 1987; 317:1565-70 21 Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of hlgh-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med 1987; 317:659-65 22 Bone RC, Slotman G, Maunder R, Silverman H, Hyers TM, Kerstein MD, et al. Randomized double-blind, multicenter study of prostaglandin E I in patients with the adult respiratory distress syndrome. Chest 1989; 96:114-19

940

23 Ziegler EJ, Fisher CJ Jr, Sprung CL, Straube RC, Sadoff JC, Foulke GE, et al. Treatment of gram-negative bacteremia and septic shock with HA-IA human monoclonal antibody against endotoxin: a randomized, double-blind, placebo-controlled trial. N Engl J Med 1991; 324:429-36 24 Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, et al. Septic shock in humans. Ann Intern Med 1990; 113:227-42 25 Morrison DC, Kline LF. Activation of the classical and properidin pathways of complement by bacterial lipopolysaccharide (LPS). J Immunol 1977; 118:362-68 26 Brigham KL, Meyrick B. Endotoxin and lung injury. Am Rev Respir Dis 1987; 133:913-27 27 Christman JW, Petras SF, Vacek PM, Davis GS. Rat alveolar macrophage production of chemoattractants for neutrophils: response to Escherichia coli endotoxin. Infect Immun 1989; 57:810-16 28 Brigham KL, Meyrick B, Berry Le, Repine JE. Antioxidants protect cultured bovine lung endothelial cells from injury by endotoxin. J Appl Physiol 1987; 63:840-50 29 Worthen GS, Haslett C, Rees AJ, Gumbay RS, Henson JE, Henson PM. Neutrophil-mediated pulmonary vascular injury. Am Rev Respir Dis 1987; 136:19-28 30 Haslett C, Worthen GS, Giclas PC, Morrison DC, Henson JE, Henson PM. The pulmonary vascular sequestration of neutrophils in endotoxemia is initiated by an effect of endotoxin on the neutrophil in the rabbit. Am Rev Respir Dis 1987; 136:918 31 Smedley LA, Tonnesen MG, Sandhaus RA, Haslett C, Guthrie LA, Johnston RB. Neutrophil-mediated injury to endothelial cells. J Clin Invest 1986; 77:1233-43 32 Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC et al. Anti-cachectinlfNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987; 330:662-64 33 Harlan JM, Harker LA, Reidy MA, Gajdusek CM, Schwartz SM, Striker GE. Lipopolysaccharide-mediated bovine endothelial cell injury in vitro. Lab Invest 1983; 48:269-74 34 Luderitz 0, 'Ianamoto K, Golanos C, McKenzie GR, Brade H, Zahringer U, et al. Lipopolysaccharides: structural principles and biologic activities. Rev Infect Dis 1984; 6:428-31 35 McCabe WR. Immunization with R mutants of S. minnesota: protection against challenge with heterologous gram-negative bacilli. J Immunol 1972; 108:601-10 36 Young LS, Stevens P, Ingram J. Functional role of antibody against "core" glycolipid of enterobacteriaceae. J Clin Invest 1975; 56:850-61 37 Dunn DL, Ferguson RM. Immunotherapy of gram-negative sepsis: enhanced survival in a guinea pig model by use of rabbit anti-serum to Escherichia coli J5. Surgery 1982; 92:21219 38 Marks MI, Zeigler EJ, Douglas H, Corbeil LB, Braude AI. Induction of immunity against lethal Haemophilus injluenzae type b infection by Escherichia coli core lipopolysaccharide. J Clin Invest 1982; 69:742-49 39 Ziegler EJ, M<.Cutchan A, Fierer J, Glauser Mp, Sadoff JC, Douglas H, et al. Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. N Engl J Med 1982; 307:1225-30 40 Baumgartner JD, McCutchanJA, Van MelleG, Vo~ M, Luethy R, Glauser Mp, et al. Prevention of gram-negative shock and death in surgical patients by antibody to endotoxin core glycolipid. Lancet 1985; 2:59-63 41 Teng NNH, Kaplan HS, Hebert JM, Moore C, Douglas H, Wunderlich A, et al. Protection against gram-negattve bacteremia and endotoxemia with human monoclonallgM antibodies. Proc Nat! Acad Sci USA 1985; 82:1790-94 42 Feeley nv, Minty BD, Scudder CM, Jones JG, Royston D, Immunologic Therapy lor ARDS (St. John, Dorinsky)

43

44

45

46

47

48

49

50 51 52

53 54 55 56

57 58 59

60

61

Teng NNH. The effect of human antiendotoxin monoclonal antibodies on endotoxin-induced lung injury in the rat. Am Rev Respir Dis 1987; 135:665-70 Dunn DL, Bogard WC, Cerra FB. Efficacy of type-specific and cross-reactive murine monoclonal antibodies directed against endotoxin during experimental sepsis. Surgery 1985; 98:283-89 Priest Bp, Brinson DN, Schroeder DA, Dunn DL. Treatment of experimental gram-negative bacterial sepsis with murine monoclonal antibodies directed against lipopolysaccharide. Surgery 1989; 106:147-55 Silva AT, Appelmelk BJ, Buurman WA, Bayston KF, Cohen J. Monoclonal antibody to endotoxin core protects mice from Escherichia coli sepsis by a mechanism independent of tumor necrosis factor and interleukin-6. J Infect Dis 1990; 162:45459 Greisman SE, Johnston CA. Failure of antisera to J5 and R595 rough mutants to reduce endotoxin lethality. J Infect Dis 1988; 157:54-64 Calandra T, Glauser MP, Schellekeas J, Verhoef J. Treatment of gram-negative septic shock with human IgG antibody to Escherichia coli J5: a prospective, double-blind, randomized trial. J Infect Dis 1988; 158:312-19 Greenman RL, Schein RMH, Martin MA, Wenzel Rp, MacIntyre NR, Emmanuel G, et aI. A controlled clinical trial of E5 murine monoclonal antibody to endotoxin in the treatment of gram-negative sepsis. JAMA 1991; 266:1097-102 Wolff SM. Monoclonal antibodies and the treatment of gramnegative bacteremia and shock. N Engl J Med 1991; 324:48687 Bone RC. Monoclonal antibodies to endotoxin. JAMA 1991; 266:1125-26 Bone RC. A critical evaluation of new agents for the treatment of sepsis. JAMA 1991; 266:1686-91 Wenzel R, Bone R, Fein A, Quenzer R, Schentag J, Gorelick KJ, et al. Results of a second double-blind, randomized, controlled trial of antiendotoxin antibody E5 in gram-negative sepsis [abstract]. Program and Abstracts of the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy, 1991; 1:294 Advisory Committee. Open meeting of the vaccine and related biological products advisory committee, September 4th, 1991. Food and Drug Administration 1991; 1:39-44 Wenzel RP. Anti-endotoxin monoclonal antibodies: a second look. N Engl J Med 1992; 326:1151-53 Warren HS, Danner RL, Mumford RS. Anti-endotoxin monoclonal antibodies. N Engl J Med 1992; 326:1153-57 Wenzel Rp, Andriole VT, Bartlett JG, Batt MD, Bullock WE, Cobbs CG, et aI. Antiendotoxin monoclonal antibodies for gram-negative sepsis: guidelines from the IDSA. Clin Infect Dis 1992; 14:973-76 Ziegler EJ, Smith CR. Anti-endotoxin monoclonal antibodies. N Engl J Med 1992; 326:1165 Beutler BA, Milsark IW; Cerami A. Cachectin/tumor necrosis factor: production, distribution, and metabolic fate in vivo. J Immunoll985; 135:3972-77 Hesse DG, Tracey KJ, Fong Y, Monogue KR, Palladino MA, Cerami A, et al. Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet 1988; 166:14753 Michie HR, Manogue KR, Spriggs DR, Revhaug A, O'Dwyer S, Dinarello CA, et aI. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318:1481-86 Cannon JG, Tompkins RG, Gelfand JA, Michie HR, Stanford GG, van der Meer JWM, et aI. Circulating interleukin-I and tumor necrosis factor in septic shock and experimental endo-

toxin fever. J Infect Dis 1990; 161:79-84 62 DeForge LE, Nguyen DT, Kunkel SL, Remick DG. Regulation of the pathophysiology of tumor necrosis factor. J Lab Clin Med 1990; 116:429-38 63 Tracey KJ, Lowry SF, Cerami A. CachectinITNF-a in septic shock and septic adult respiratory distress syndrome. Am Rev Respir Dis 1988; 138:1377-79 64 Mathison JC, Wolfson E, Ulevitch RJ. Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest 1988; 81:1925-37 65 Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW; et al. Shock and tissue injury induced by recombinant human cachectin. Science 1986; 234:470-74 66 Remick DG, Kunkel RG, Larrick JW; Kunkel SL. Acute in vivo effects of human recombinant tumor necrosis factor. Lab Invest 1987; 86:583-90 67 Wewers MD, Rinehart JJ, She ZW; Herzyk DJ, Hummel MM, Kinney PA, et aI. Tumor necrosis factor infusions in humans prime neutrophils for hypochlorous acid production. Am J Physiol Lung (Cell Mol Physiol) 1990; 259:L76-82 68 Stephens KE, Ishizaka A, Larrick JW; Raffin TA. Tumor necrosis factor causes increased pulmonary permeability and edema: comparison to septic acute lung injury. Am Rev Respir Dis 1988; 137:1364-70 69 Gamble JR, Harlan JM, KlebanoffSJ, Vadas MA. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci USA 1985; 82:8667-71 70 Cotran RS, Kumar V, Robbins SL, eds. Robbins' pathologic basis ofdisease, 4th ed. New York, Harcourt Brace Jovanovich, 1989; 39-71 71 Hinshaw LB, Tekamp-Olsen P, Chang AC, Lee PA, Taylor FB, Murray CK, et al. Survival of primates in LDl00 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha). Circ Shock 1990; 30:279-92 72 Beutler B, Milsark lW; Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from the lethal effect of endotoxin. Science 1985; 229:869-71 73 Exley AR, Cohen J, Buurman W; Owen R, Hanson G, Lumley J, et aI. Monoclonal antibody to TNF in severe septic shock. Lancet 1990; 335: 1275-77 74 Marks JD, Marks CB, Luce JM, Montgomery AB, Turner J, Metz CA, et aI. Plasma tumor necrosis factor in patients with septic shock. Am Rev Respir Dis 1990; 141:94-7 75 Waage A, Halstensen A, Espevik T. Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet 1987; 1:355-57 76 Offner F, Phillipe J, Vogelaers D, Colardyn F, Baele G, Baudrihaye M, et al. Serum tumor necrosis factor levels in patients with infectious disease and septic shock. J Lab Clin Med 1990; 116:100-05 77 Calandra T, Baumgartner JD, Grau GE, Wu MM, Lambert PH, Schellekens J, et aI. Prognostic values of tumor necrosis factor/cachectin, interleukin-L, interferon-a, and interferon-g in the serum of patients with septic shock. J Infect Dis 1990; 161:982-87 78 de Groote MA, Martin MA, Densen P, Pfaller MA, Wenzel RP. Plasma tumor necrosis factor levels in patients with presumed sepsis. JAMA 1989; 262:249-51 79 Fong Y, Tracey KJ, Moldawer LL, Hesse DG, Manogue KB, Kenney JS, et aI. Antibodies to cachectin/tumor necrosis factor reduce interleukin Ib and interleukin 6 appearance during lethal bacteremia. J Exp Med 1989; 170:1627-33 80 Lechner AJ, Klein CA, Schilly DR, Nye cv Matuschak GM. Differential host responses to C. olbicans fungemia and E. coli bacteremia in conscious rats: effects of anti-TNF-a antiserum CHEST I 103 I 3 I MARCH, 1993

941

81

82

83 84 85

86

87

88

89 90

91

92

93

94 95 96

97

98 99

942

or ibuprofen on formed blood elements, mortality, and organ damage [abstract]. Am Rev Respir Dis 1991; 143:A682 Silva AT, Bayston KF, Cohen J. Prophylactic and therapeutic effects of a monoclonal antibody to tumor necrosis factor-a in experimental gram-negative shock. J Infect Dis 1990; 162:42127 Arend WP. Interleukin 1 receptor antagonist. J Clin Invest 1991; 88:1445-51 Dinarello CA, Interleukin-l and interleukin-l antagonism. Blood 1991; 77:1627-52 Dinarello CA. Biology of interleukin 1. FASEB J 1988; 2:10815 Okusawa S, Celfand JA, Ikejima T, Connolly RJ, Dinarello CA. Interleukin 1 induces a shock-like state in rabbits. J Clin Invest 1988; 81:1162-72 Cranowitz EV,Santos AA, Poutsiaka DD, Cannon JC, Wilmore DW Wo1fT SM, et aI. Production of interleukin-l-receptor antagonist during experimental endotoxaemia. Lancet 1991; 338:1423-24 Spinas CA, Bloesch D, Kaufmann MT, Keller U, Dayer JM. Induction of plasma inhibitors of interleukin 1 and TNF-a activity by endotoxin administration to normal humans. Am J Physiol (Regullntegr Comp Physiol) 1990; 259:R993-97 Dripps DJ, Brandhuber BJ, Thompson RC, Eisenberg SP. Interleukin-l (IL-l) receptor antagonist binds to the 8O-kDa IL-l receptor but does not initiate IL-l signal transduction. J BioI Chern 1991; 266:10331-336 Hannum CH, Wilcox CJ, Arend Wp, Joslin FC, Dripps DJ, Heimdal PL, et aI. Interleukin-l receptor antagonist activity of a human interleukin-l inhibitor. Nature 1990; 343:336-40 Eisenberg Sp' Evans RJ, Arend Wp, Verderber E, Brewer MT, Hannum CH, et aI. Primary structure and functional expression from complementary DNA of a human interleukin-l receptor antagonist. Nature 1990; 343:341-46 Wakabayashi C, Celfand JA, Burke JF, Thompson RC, Dinarello CA. A specific receptor antagonist for interleukin 1 prevents Escherichia coli-induced shock in rabbits. FASEB J 1991; 5:338-43 Alexander HR, Donerty CM, Buresh CM, Venzon DJ, Norton JA. A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. J Exp Med 1991; 173:1029-32 Ulich TR, Yin S, Cuo K, Del Castillo J, Eisenberg Sp' Thompson RC. The intratracheal administration of endotoxin and cytokines: III. The interleukin-l (IL-l) receptor antagonist inhibits endotoxin- and IL-l-induced acute inflammation. Am J Patholl991; 138:521-24 Ohlsson K, Bjork P, Bergenfeldt M, Hageman R, Thompson RC. Interleukin-l receptor antagonist reduces mortality from endotoxin shock. Nature 1990; 348:550-52 HC, Thompson RC, Eisenberg SP. BiologArend WP, ~Igus ical properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest 1990; 85:1694-97 Cordon CS, Fisher CJ, Slotman CJ, Opal SM, Pribble JP, Stiles DM, et aI. Cost-effectiveness of treatment with interleukin-l receptor antagonist (IL-lra) in patients with sepsis syndrome [abstract]. Clin Res 1992; 40:254A Strieter RM, Chenuse SW Basha MA, Standiford TJ, Lynch JP, Baggiolini M, et aI. Human alveolar macrophage gene expression of interleukin-8 by tumor necrosis factor-a, Iipopolysaccbaride, and interleukin-lb. Am J Respir Cell Mol BioI 1900; 2:321-26 Baggiolini M, WaIz A, Kunkel SL. Neutrophil-activating peptide-l/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest 1989; 84:1045-49 Leonard EJ, Yoshimura T. Neutrophil attractant/activation protein-I (NAill [interleukin-8]). Am J Respir Cell Mol BioI

1990; 2:479-86 100 Van Zee KJ, DeForge LE, Fischer E, Marano MA, Kenney JS, Remick DC, et aI. IL-8 in septic shock, endotoxemia, and after lL-l administration. J Immunoll991; 146:3478-82 101 Danner RL, Suffredini AF, Van Dervort AL, Ceska M, Stuetz PL, Zablotny JA, et aI. Detection of interleukin 6 (IL-6) and interleukin 8 (IL-8) during septic shock in humans [abstract]. Clin Res 1990; 38:352A 102 Martich CD, Danner RL, Ceska M, Suffredini AF. Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents. J Exp Med 1991; 173:1021-24 103 Cohen AB, Macarthur C, Idell S, Maunder R, Martin T, Dinarello CA, et aI. A peptide from alveolar macrophages that releases neutrophil enzymes into the lungs in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1988; 137:1151-58 104 Miller EJ, Cohen AB, Maunder R, Martin T. Neutrophil activating factor concentration is increased in bronchoalveolar lavage fluids (BALF) from some patients with adult respiratory distress syndrome [abstract]. Am Rev Respir Dis 1990; 141:A95 lOS Matthay MA, Miller EJ, Wiener-Kronish If; Cohen A. Elevated levels of neutrophil activating factor in the pulmonary edema fluid of patients with the adult respiratory distress syndrome (ARDS) [abstract]. Am Rev Respir Dis 1990; 141:A97 106 Cimbrone MA, Obin MS, Brock AF, Luis EA, Hass PE, Hebert CA, et aI. Endothelial interleukin 8: a novel inhibitor ofleukocyte-endothelial interactions. Science 1989; 246:160103 107 Detmers PA, Lo SK, Olsen-Egbert E, WaIz R, Baggiolini M, Cohn ZA. Neutrophil-activating protein l/interleukin 8 stimulates the binding activity of the leukocyte adhesion receptor CDUb/CD18 on human neutrophils. J Exp Med 1990; 171:1155-62 lOS Carveth HJ, BohnsackJF, McIntyreTM, Baggiolini M, Prescott SM, Zimmerman CA. Neutrophil activating factor (NAF) induces polymorphonuclear leukocyte adherence to endothelial cells and to subendothelial matrix proteins. Biochem Biophys Res Commun 1989; 162:387-93 109 Wong CC, Clark SC. Multiple actions of interleukin 6 within a cytokine network. Immunol Today 1988; 9:137-39 110 Hack CE, De Croot ER, Felt-Bersma RJF, Nuijens JH, Strack Van Schijndel RJM, Eerenberg-Belmer AJM, et aI. Increased plasma levels of interleukin-6 in sepsis. Blood 1989; 74:170410 III Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. J Exp Med 1989; 169:333-38 112 Brouckaert P, Spriggs DR, Demetri C, Kufe DW Fiers \v. Circulating interleukin 6 during a continuous infusion of tumor necrosis factor and interferon g. J Exp Med 1989; 169:2257-62 113 Fong Y, Moldawer LL, Marano M, Wei H, Tatter SB, Clarick RH, et aI. Endotoxemia elicits increased circulating g2-IFNI IL-6 in man. J Immunoll989; 142:2321-24 114 Starnes HF, Pearce MK, Tewari A, Yim JH, Zou JC, Abrams JS. Anti-IL-6 monoclonal antibodies protect against lethal Escherichia coli infection and lethal tumor necrosis factor-a challenge in mice. J Immunoll990; 145:4185-91 115 Johnston J. Molecular science sets its sights on septic shock. J Natl Inst Health Res 1991; 3:61-5 116 Suzuki H, YasukawaK, Saito T, Anzai M, Coitsuka R, Hasegawa A, et aI. Anti-murine IL-6 receptor antibody inhibits IL-6 effects in vivo. Immunol Lett 1991; 30:17-21 117 Marra MN, Wilde CC, Collins MS, Snable JL, Thornton MB, Scott mv. The role of bactericidal/permeability-increasing protein as a natural inhibitor of bacterial endotoxin. J Immunol 1992; 148:532-37 Immunologic Therapy lor ARDS (Sf. John, Dorinsky)

118 Mannion BA, Weiss J, Elsbach P. Separation of sublethal and lethal effects of the bactericidal/permeability increasing protein on Escherichia coli. J Clin Invest 1990: 85:853-60 119 Taylor FB, Chang A, Morrissey JH, Hinshaw L, Catlett R, Blick K, et aI. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991: 33:127-34 120 Taylor FB, Chang A, Esmon CT, D'Angelo A, Vigano-D'Angelo S, Blick KE. Protein C prevents coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987: 79:918-25 121 Weiland JE, Davis WB, Holter JF, Mohammed JR, Dorinsky PM, Gadek JE. Lung neutrophils in the adult respiratory distress syndrome. Am Rev Respir Dis 1986: 133:218-25 122 Weiss SJ. TIssue destruction by neutrophils. N Engl J Med 1989: 320:365-76 123 Wewers MD, Herzyk DJ, Gadek JE. Alveolar Buid neutrophil elastase activity in the adult respiratory distress syndrome is complexed to alpha-2-macroglobulin. J Clin Invest 1988: 82:1260-67 124 Lee CT, Fein AM, Lippman M, Holtzman H, Kimbel P, Wienbaum G. Elastolytic activity in pulmonary lavage Buid from patients with adult respiratory distress syndrome. N Engl J Med 1981: 304:192-96 125 Craddock PR, Fehr J, Brigham KL, Kronenberg RS, Jacob HS. Complement and leukocyte-mediated pulmonary dysfunction in hemodialysis. N Engl J Med 1977: 296:769-74 126 Rinaldo JE, Henson JE, Dauber JH, Henson PM. Role of alveolar macrophages in endotoxin-induced neutrophilic alveolitis in rats. TIssue Cell 1985: 17:461-72 127 Davis WB, Mohammed JR, Mohammed BS, Baker NR. Neutrophil myeloperoxidase: a mediator of airway epithelial damage [abstract]. Clin Res 1986: 34:934A 128 St. John RC, Dorinsky PM. Increased protein permeability in the cat ileum after acid aspiration-induced acute lung injury: evidence for systemic endothelial injury [abstract]. Am Rev Respir Dis 1991: 143:A805 129 Argenbright L\v, Letts LG, Rothlein R. Monoclonal antibodies to the leukocyte membrane CD18 glycoprotein complex and to intercellular adhesion moleeule-I inhibit leukocyte-endothelial adhesion in rabbits. J Leukoc BioI 1991: 49:253-257 130 Amaout MA. Structure and function of the leukocyte adhesion molecules CDIl/CDI8. Blood 1990: 75:1037-50 131 Springer SA. Adhesion receptors of the immune system. Nature 1990: 346:425-34 132 Pohlman TH, Stanness KA, Beatty PG, Ochs HD, Harlan JM. An endothelial cell surface factor(s) induced in vitro by

lipopolysaccharide, interleukin I, and tumor necrosis factor-a increases neutrophil adherence by a CDw-18-dependent mechanism. J Immunoll986: 136:4548-53 133 Horgan MJ, Wright SD, Malik AB. Antibody against leukocyte integrin (CDI8) prevents reperfusion-induced lung vascular injury. Am J Physiol (Lung Cell Mol Physiol) 1990: 259:L31519 134 Simpson PJ, Fantone JC, Mickelson JK, Griffin JD, Lucchesi BR. Reduction of experimental canine myocardial reperfusion injury by a monoclonal antibody (anti-Mol, anti-CDllb) that inhibits leukocyte adhesion. J Clin Invest 1988: 81:624-29 135 Hernandez LA, Grisham MB, Twohig B, Arfors KE, Harlan JM, Granger DN. Role of neutrophils in isehemia-reperfusioninduced microvascular injury. Am J Physiol (Heart Circ Physiol) 1987: 253:H699-703 136 Ismail G, Morganroth ML, Todd RF, Boxer LA. Prevention of pulmonary injury in isolated perfused rat lungs by activated human neutrophils preincubated with anti-Mol monoclonal antibody. Blood 1987: 69:1167-74 137 Vedder NB, Winn RK, Rice CL, Chi EY, Arfors KE, Harlan JM. A monoclonal antibody to the adherence-promoting leukocyte glycoprotein, CD18, reduces organ injury and improves survival from hemorrhagic shock and resuscitation in rabbits. J Clin Invest 1988; 81:939-44 138 Mileski WJ, Winn RK, Vedder NB, Pohlman TH, Harlan JM, Rice CL. Inhibition of CD18-dependent neutrophil adherence reduces organ injury after hemorrhagic shock in primates. Surgery 1990: 108:206-12 139 Walsh CJ, Carey PD, Cook DJ, Bechard DE, Fowler AA, Sugerman HJ. Anti-CDI8 antibody attenuates neutropenia and alveolar capillary-membrane injury during gram-negative sepsis. Surgery 1991; 110:205-12 140 Walsh CJ, Leeper-Woodford SK, Carey PD, Cook DJ, Bechard DE, Fowler AA, etal. CD18 adhesion receptors, tumor necrosis factor, and neutropenia during septic lung injury. J Surg Res 1991; 50:323-29 141 Thomas JR, Gleich MC, Harlan JM, Rice CL, Winn RK. Inhibition of neutrophil (PMN) adherence by anti-CD18 monoclonal antibody (MAB) does not prevent acute lung injury in endotoxemia [abstract]. Am Rev Respir Dis 1991; 143:A542 142 St. John RC, Dorinsky PM. Inhibition of neutrophil adherence does not prevent systemic organ injury during PMA-induced acute lung injury [abstract]. Am Rev Respir Dis 1991: 143:A682 143 Sharar SR, Winn RK, Murry CE, Harlan JM, Rice CL. A CD18 monoclonal antibody increases the incidence and severity of subcutaneous abscess formation after high-dose Staphylococcus aureus injection in rabbits. Surgery 1991: 110:213-20

CHEST I 103 I 3 I MARCH. 1993

943