The terminal complement complex (sC5b-9) is not specifically associated with the development of the adult respiratory distress syndrome

Previous investigators suggested that increased plasma levels of the terminal complement complex (sC5b-9) are an early marker for the development of adult respiratory distress syndrome (ARDS) in septic patients. We asked whether an increase in sC5b-9 was also associated with the development of ARDS from other etiologies and whether sC5b-9 measurements consistently reflected complement activation in vivo. We evaluated 75 patients with sepsis, trauma, hypertransfusion, multiple fractures, aspiration, or pancreatitis who were at risk for ARDS but did not develop the syndrome and 23 patients with similar histories who did develop ARDS. Of the latter patients, seven were identified and studied both when they were at risk and when they had ARDS. Serial blood samples were obtained and analyzed for the complement activation products Bb, Ba, C4d, C3d, IC3b, and sC5b-9. All but one of the patients studied had levels of one or more complement fragments that were greater than 2 SD above the mean obtained from 18 normal subjects. In contrast to the report referred to previously, none of the fragments measured, including sC5b-9, was a specific indicator of ARDS, and no combination of complement fragments predicted which patients at risk would develop ARDS. Patients demonstrated evidence of activation of the classical pathway only, alternative pathway only, or both pathways, but none of these was associated with greater risk or severity of disease. In addition, in several patients only late components were activated, suggesting that enzymes other than those derived from complement activation may be responsible. In conclusion, complement can be activated by a variety of mechanisms in critically ill patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Accentuated complement activation in patient plasma during the adult respiratory distress syndrome: a potential mechanism for pulmonary inflammation

The adult respiratory distress syndrome (ARDS) represents an acute inflammatory lung disorder, characterized by both refractory hypoxemia and a mortality rate approaching 95%. Researchers have proposed that activation of the complement (C) system may play a role in the development of the pulmonary inflammation associated with ARDS. The purpose of this investigation was to determine whether complement activation occurs to a greater extent in patients with ARDS than in patients without ARDS, thereby providing a potential mechanism for the acute inflammation seen in ARDS. In this study, we assessed plasma complement activation by measuring complement activation by-products: C1rC1s-C1 inhibitor complex and C3b-P complex, generated subsequent to activation of the classical and alternative pathways, respectively, and also the terminal complement complex, formed after activation of either the classical or alternative complement pathway. Multivariate discriminant analysis revealed that these three complement activation complexes could distinguish patients with ARDS from those without ARDS (p less than 0.04). Furthermore, these three complexes provided a more sensitive discriminator of ARDS than did plasma levels of C3a desarginine (p greater than 0.30), C5a desarginine (p greater than 0.41) and total hemolytic complement activity (CH50) (p greater than 0.72). We conclude that a temporal association exists between the complement activation and the development of ARDS. Therefore, we suggest that complement activation by-products be included in the armamentarium for ARDS.     

Molecular weight of the membrane C5b-9 complex of human complement: characterization of the terminal complex as a C5b-9 monomer.

The hydrodynamic properties of the detergent-solubilized, terminal membrane complex of serum complement components C5-C9 [C5b-9(m)] were studied to obtain an estimate of its molecular weight. In a solution of Triton X-100/deoxycholate, the protein complex binds 17% Triton X-100 and 11% deoxycholate by weight. The sedimentation coefficient of the protein-detergent complex is 26 S as determined by sucrose density gradient ultracentrifugation, and gel filtration indicated a molecular radius of 11 nm. It was ascertained by electron microscopy that these hydrodynamic parameters apply to mono-dispersed C5b-9(m) complexes, which were observed as nonaggregated, hollow protein cylinders and were identical to the complement "lesions" formed on target membranes. The calculated molecular weight of the protein-detergent complex is approximately 1,286,300 to which the protein moiety contributes approximately 1,000,000. The results indicate that the C5b-9(m) complex formed on biological membranes is a monomer entity of the C5-C9 complement components.     

Immunoelectron-microscopic localization of the terminal C5b-9 complement complex in human atherosclerotic fibrous plaque

The assembly of the terminal C5b-9 complement complex is a prime mechanism of complement-induced membrane damage followed by inflammatory response mediation and subsequent extensive tissue damage. In the assembly process the terminal complement components expose neoantigenic determinants which can be recognized by specific antibodies. Using such a specific antibody, affinity-purified rabbit IgG and by means of immunoelectron microscopy, the C5b-9 neoantigens were localized on the structures of the human fibrous plaque from 3 iliac and 3 femoral arteries obtained at surgery. The immunoelectron-dense deposits were localized on the cell debris, enmeshed in the connective tissue matrix, consisting of irregular particles that frequently had the shape and size of intracellular organelles or vesicles with concentric osmiophilic lamellae. No deposits could be found on the intact cells, on the connective tissue matrix or on cholesterol and lipid deposits. The presence of C5b-9 neoantigens deposits in the fibrous plaques frequently associated with other immune-related proteins indicates that complement activation has occurred in situ and could be related to the chronic progression of the atherosclerotic lesion.     

Immunohistochemical localization of the terminal C5b-9 complement complex in human aortic fibrous plaque

The terminal C5b-9 complex of the complement system was localized in 26 aortic, 3 iliac and 4 femoral human fibrous plaques using indirect immunofluorescence and immunoperoxidase. IgG, IgA, IgM, Clq, C3c, C4, C9 and fibrinogen were investigated simultaneously. All the fibrous plaques presented C5b-9 deposits appearing like thin threads in the fibrous cap and masses and spots in the amorphous areas. The extent and intensity were in agreement with the size of the fibrous plaques. The intimal thickenings presented less intense deposits which were absent in atherosclerosis-free samples. The C5b-9 deposits were frequently associated with immunoglobulins and complement components in the same areas. Whereas the demonstration of complement components reflected only a nonspecific trapping, the presence of assembled C5b-9 in the damaged tissues is more indicative of the involvement of complement activation in the tissue injury. The absence of C5b-9 in the atherosclerosis-free intima and its presence at lower intensity in the intimal thickenings than in the fibrous plaques suggest a pathogenic involvement in the chronic progression of the atherosclerotic lesion.     

Deposition of the terminal C5b-9 complement complex on erythrocytes by human red cell autoantibodies

A radioassay for the detection of complement activating autoantibodies (autohaemolysins) in patients with autoimmune haemolytic anaemia (AIHA) is described. The method is based on immunoradiometric quantitation of the cytolytic C5b-9 complement complex following its antibody-dependent deposition on red blood cells (RBC). The use of affinity-purified, radiolabelled antibodies directed against the neoantigens of the C5b-9 complex ensured specificity of the test which proved more sensitive than conventional haemolytic assays and was not subject to disturbances by haemolytic sera.
The results obtained in 70 patients with various forms of AIHA (warm type ( N = 45); cold type ( N = 22); Donath-Landsteiner type ( N = 3)) support the prevailing assumption that autohaemolysins can trigger the complement cascade to completion. Since intact RBC from patients with detectable autohaemolysins carried C3/C4 components but never C5b-9, it is inferred that regulatory mechanisms operate in vivo at the level of C4b/C3b inactivation to arrest the cascade and rescue the autologous cells.     

Evidence for a two-domain structure of the terminal membrane C5b-9 complex of human complement.

Lipid vesicles carrying the purified membrane C5b-9 complex [C5b-9(m)] of complement were analyzed immunochemically and in the electron microscope after treatment with a combination of trypsin and alpha-chymotrypsin. Under reducing conditions, the externally oriented annulus was removed. The remaining part of the C5b-9(m), representing approximately half of the total mass of the macromolecular complex, was visualized in the electron microscope as a hollow cylindrical structure with walls of 1-nm thickness. This structure remained tenaciously attached to the lipid bilayer, projecting 8-9 nm from the external membrane surface into the aqueous environment. Cleavage of C5b-9(m) by proteolysis and reduction resulted in a sharp reduction of tis antigenic determinants. One hydrophilic protease-resistant C5 derivative was released from the membrane and recovered in the fluid phase. The membrane-bound residue almost totally lacked antigens precipitable with antisera to C5, C6, C9, and C5b-9(m).     

The cytolytic C5b-9 complement complex: feedback inhibition of complement activation

We describe a regulatory function of the terminal cytolytic C5b-9 complex [C5b-9(m)] of human complement. Purified C5b-9(m) complexes isolated from target membranes, whether in solution or bound to liposomes, inhibited lysis of sensitized sheep erythrocytes by whole human serum in a dose-dependent manner. C9 was not required for the inhibitory function since C5b-7 and C5b-8 complexes isolated from membranes were also effective. No effect was found with the cytolytically inactive, fluid-phase SC5b-9 complex. However, tryptic modification of SC5b-9 conferred an inhibitory capacity to the complex, due probably to partial removal of the S protein. Experiments using purified components demonstrated that C5b-9(m) exerts a regulatory effect on the formation of the classical- and alternative-pathway C3 convertases and on the utilization of C5 by cell-bound C5 convertases. C5b-9(m) complexes were unable to inhibit the lysis of cells bearing C5b-7(m) by C8 and C9. Addition of C5b-9(m) to whole human serum abolished its bactericidal effect on the serum-sensitive Escherichia coli K-12 strain W 3110 and suppressed its hemolytic function on antibody-sensitized, autologous erythrocytes. Feedback inhibition by C5b-9(m) represents a biologically relevant mechanism through which complement may autoregulate its effector functions.     

Multimeric complement component C9 is necessary for killing of Escherichia coli J5 by terminal attack complex C5b-9.

We studied the molecular composition of the complement C5b-9 complex required for optimal killing of Escherichia coli strain J5. J5 cells were incubated in 3.3%, 6.6%, or 10.0% C8-deficient serum previously absorbed to remove specific antibody and lysozyme. This resulted in the stable deposition after washing of 310, 560, and 890 C5b67 molecules per colony-forming unit, respectively, as determined by binding of 125I-labeled C7. Organisms were then incubated with excess C8 and various amounts of 131I-labeled C9. Plots of the logarithm (base 10) of E. coli J5 cells killed (log kill) vs. C9 input were sigmoidal, confirming the multihit nature of the lethal process. When C9 was supplied in excess, 3300, 5700, and 9600 molecules of C9 were bound per organism for cells bearing 310, 560, and 890 C5b-8 complexes, respectively, leading to C9-to-C7 ratios of 11.0:1, 10.8:1, and 11.4:1 and to log kill values of 1.3, 2.1, and 3.9. However, at low inputs of C9 that lead to C9-to-C7 ratios of less than 3.3:1, no killing occurred, and this was independent of the number of C5b-9 complexes bound. Formation of multimeric C9 at C9-to-C7 ratios permissive for killing was confirmed by electron microscopy and by binding of 125I-labeled antibody with specificity for multimeric but not monomeric C9. These experiments are the first to demonstrate a biological function for C9 polymerization and suggest that multimeric C9 is necessary for optimal killing of E. coli J5 cells by C5b-9.     

Terminal complement complex (C5b-9) in children with recurrent hemolytic uremic syndrome

Recurrent hemolytic uremic syndrome (recHUS) is a heterogeneous group of disorders. The pathogenesis of recHUS is not fully understood. recHUS has a high risk of development of terminal renal insufficiency and other sequelae. Abnormalities in complement factor H or in membrane-bound complement inhibitors with consecutive complement activation can be found in approximately 30 to 50% of the patients. Starting in 2001, we evaluated 42 patients with recHUS from five European countries (Germany, Austria, Hungary, Switzerland, and the Czech Republic). We measured the terminal complement complex (TCC) by an enzyme-linked immunosorbent assay using a neoepitope-specific anti-C9 antibody in 17 patients in plasma (native complement activation), serum (after coagulation), and zymosan-activated serum (Z-serum; after stimulation of coagulation). We compared the results to those of 16 healthy persons. In patients with recHUS (eight males, nine females) with a median age of 10.8 years, the TCC values were higher in plasma (0.57 versus 0.48 microg/mL; P = 0.04) and serum (3.1 versus 2.2 microg/mL) than in those of the control group, with a median age of 28.6 years (six males, 10 females) The TCC values in patients with low C3 compared with patients with normal C3 levels were even higher in plasma and serum, and the ratio was much lower. Children with recHUS have higher concentrations of TCC in plasma and serum. The ratio of Z-serum to serum showed significantly lower values in children with recHUS (96.01 versus 150.3; P = 0.01). These findings indicate a higher grade of complement activation and consumption in recHUS, suggesting that TCC may mediate cell toxicity. This may play an important role in the inferior outcome of these patients. The isolated substitution of factor H, or other complement inhibitors to block TCC formation, may represent useful therapies for these patients.     

雷公藤甲素干预C5b-9诱导足细胞损伤的体外研究

目的:体外观察雷公藤甲素对膜攻击复合物C5b-9介导的足细胞损伤的影响,探讨雷公藤甲素治疗膜性肾病的疗效机制. 方法:以纯化的C5b6及C7～C9体外组装C5b-9,建立足细胞亚溶破模型.免疫荧光染色分析C5b-9对足细胞骨架相关蛋白F-actin表达和分布的影响;在观察雷公藤甲素对C5b-9导致的足细胞损伤的治疗机制研究中,免疫荧光观察和流式细胞仪定量分析雷公藤甲素对C5b-9在足细胞膜上组装和活性的影响.并进一步在C5b-9组装完成后加入雷公藤甲素,观察雷公藤甲素对C5b-9诱导的足细胞内活性氧(ROS)和丝裂原活化蛋白激酶(MAPK)信号通路的影响.流式细胞仪分析荧光探针CM-H2DCFDA标记的细胞内ROS,MAPK信号通路的活性采用Western blot检测p-38,ERK 1/2和JNK MAPK磷酸化水平,以及MAPK信号通路选择性阻断剂SB202190,U0126和SP600125对C5b-9作用的影响. 结果:免疫荧光和LDH释放试验显示C5b-9在足细胞膜组装成功,亚溶解剂量C5b-9对足细胞膜完整性没有明显影响,但可呈时间依赖性的破坏足细胞骨架结构,表现为细胞骨架的极性消失,排列紊乱,部分足细胞F-actin的丝状结构完全消失.C5b-9可诱导足细胞内ROS的明显增加,激活p-38 MAPK信号通路,但C5b-9对ERK MAPK和JNK MAPK信号通路没有明显的影响.抗氧化剂N-乙酰半胱氨酸(NAC)、p-38 MAPK通路特异性抑制剂SB202190均能够拮抗C5b-9对足细胞的损伤,而ERK MAPK和JNK MAPK通路抑制剂U0126和sp600125对C5b-9诱导的足细胞损伤没有明显的保护作用.雷公藤甲素(10ng/ml)对C5b-9复合物在足细胞膜上组装量和活性没有明显的影响.当C5b-9在足细胞膜上组装完成后加入雷公藤甲素,雷公藤甲素对C5b-9诱导的细胞内ROS的产生没有明显的抑制作用,但能够有效遏制p-38 MAPK信号通路的活化,p-38 MAPK的磷酸化水平显著降低. 结论:雷公藤甲素的疗效机制除了免疫抑制和抗炎作用外,还可通过抑制C5b-9激活的细胞内p-38 MAPK信号通路发挥直接的足细胞保护作用.雷公藤甲素对足细胞的上述作用可能部分参与了其对膜性肾病的疗效.     

Activation of the complement system in the adult respiratory distress syndrome

The adult respiratory distress syndrome (ARDS) is an acute pulmonary disorder characterized by the accumulation of neutrophils within the lower respiratory tract. Because activation of the complement system can generate C5a, a potent neutrophil chemoattractant, complement activation was assessed in both serum and bronchoalveolar lavage fluid obtained from 10 patients with ARDS and compared with that from normal control subjects. Crossed immunoelectrophoresis was used to determine activation of the complement components C3 and properdin factor B (PFB), and radioimmunoassay was used to determine the presence of C5a. Complement activation was not detected either in the plasma or in the lung epithelial lining fluid of the control subjects. In contrast, evidence of C3 activation was found in the plasma of 50% of the patients with ARDS when initially studied; likewise, C3 activation, PFB activation, and C5a could all be detected in the epithelial lining fluid of all patients with ARDS with a single exception. Follow-up bronchoalveolar lavages revealed decreased amounts of C3 activation and C5a 2 to 7 days after the onset of ARDS, and the complement activation had resolved when the patients with ARDS had completely recovered. To determine if the C5a in bronchoalveolar lavage fluid could be responsible for the influx of neutrophils observed in ARDS, epithelial lining fluids obtained from both normal control subjects and from patients with ARDS were fractionated by molecular sieve chromatography. Two distinct fractions of chemotactic activity were found in the ARDS bronchoalveolar lavage fluid.(ABSTRACT TRUNCATED AT 250 WORDS)     

The terminal complement complex, C5b-9, a marker of disease activity in patients with systemic lupus erythematosus

Concentrations of the terminal complement complex (TCC), C5b-9, were examined in 120 serum samples from 28 patients with systemic lupus erythematosus. Eleven patients with various manifestations of the disease were followed longitudinally for a 2-year period during active and inactive phases of the disease. In 9 of the 11 patients, elevations in TCC concentrations correlated with disease exacerbations. In many of these patients, C3 and C4 levels remained normal during the study and were less sensitive indicators of disease activity than were TCC concentrations. We believe that measurements of TCC are useful in monitoring patients with rheumatic diseases in which complement activation is a component.     

Ultrastructure of the membrane attack complex of complement: detection of the tetramolecular C9-polymerizing complex C5b-8.

The ultrastructure of the membrane attack complex (MAC) of complement had been described as representing a hollow cylinder of defined dimensions that is composed of the proteins C5b, C6, C7, C8, and C9. After the characteristic cylindrical structure was identified as polymerized C9 [poly(C9)], the question arose as to the ultrastructural identity and topology of the C9-polymerizing complex C5b-8. An electron microscopic analysis of isolated MAC revealed an asymmetry of individual complexes with respect to their length. Whereas the length of one boundary (+/- SEM) was always 16 +/- 1 nm, the length of the other varied between 16 and 32 nm. In contrast, poly(C9), formed spontaneously from isolated C9, had a uniform tubule length (+/- SEM) of 16 +/- 1 nm. On examination of MAC-phospholipid vesicle complexes, an elongated structure was detected that was closely associated with the poly(C9) tubule and that extended 16-18 nm beyond the torus of the tubule and 28-30 nm above the membrane surface. The width of this structure varied depending on its two-dimensional projection in the electron microscope. By using biotinyl C5b-6 in the formation of the MAC and avidin-coated colloidal gold particles for the ultrastructural analysis, this heretofore unrecognized subunit of the MAC could be identified as the tetramolecular C5b-8 complex. Identification also was achieved by using anti-C5 Fab-coated colloidal gold particles. A similar elongated structure of 25 nm length (above the surface of the membrane) was observed on single C5b-8-vesicle complexes. It is concluded that the C5b-8 complex, which catalyzes poly(C9) formation, constitutes a structure of discrete morphology that remains as such identifiable in the fully assembled MAC, in which it is closely associated with the poly(C9) tubule.     

Detection of activated complement complex C5b-9 and complement receptor C5a in skin biopsies of patients with systemic sclerosis (scleroderma)

OBJECTIVE: Upregulated matrix synthesis is a hallmark of systemic sclerosis (SSc). There are indications that growth factors such as platelet derived growth factor (PDGF) are involved in proliferative pathways in SSc lesions. As activated complement releases PDGF from endothelial cells, we searched for activated complement and the complement receptor for C5a (C5aR) in skin biopsies of patients with SSc. METHODS: Snap frozen sections of 8 patients with early SSc and 5 patients with longterm SSc were examined. Using monoclonal antibodies against activated complement complex C5b-9 and the C5aR, skin biopsies derived from both clinically involved and non-involved skin were examined by APAAP immunohistochemistry. RESULTS: A pattern of activated complement C5b-9 and the CSaR could be detected in SSc microvasculature. Eleven of the 13 patients (7/8 patients with early SSc) showed positive staining for C5b-9. The CSaR was detected in 6 of the 8 patients with early SSc. In 3 patients with longterm disease, C5aR expression could also be detected in non-involved skin. CONCLUSION: Activated complement and complement receptors could be detected in early and late stages of SSc skin lesions. The presence of complement receptors in non-involved skin may indicate preclinical activation of pathways resulting in growth factor dependent matrix synthesis.     

Participation of protein kinases in complement C5b-9-induced shedding of platelet plasma membrane vesicles.

The formation of membrane microparticles through vesiculation of the platelet plasma membrane is known to provide catalytic surface for several enzyme complexes of the coagulation system, and to underlie the procoagulant responses elicited with platelet activation. This induced shedding of vesicles from the plasma membrane is most prominent when platelets are activated by the terminal complement proteins, C5b-9, by a Ca2+ ionophore, or by the combination of thrombin plus collagen. Although shown to require elevated [Ca2+], the cellular events that initiate plasma membrane evagination and fusion to form the shed vesicles remain unresolved. To gain additional insight into the cellular events that regulate membrane microparticle formation, we have examined how this process is influenced by the activity of cellular protein kinases. Cytoplasmic [Ca2+] of gel-filtered platelets was increased by membrane assembly of the terminal complement proteins C5b-9 in the presence of selective inhibitors of protein kinase or phosphatase reactions, and resulting microparticle formation was quantitated by fluorescence-gated flow cytometry. Pre-equilibration of the phosphatase inhibitor vanadate into the platelet cytosol increased microparticle formation by as much as 40%, suggesting that vesiculation of the platelet plasma membrane is influenced by the state of phosphorylation of a cellular constituent. By contrast to the stimulatory effects of vanadate, microparticle formation was partially inhibited in platelets treated with the protein kinase inhibitor sphingosine, the myosin light chain kinase inhibitor ML-7, the calmodulin-antagonist W-7, and under conditions of elevated cytosolic concentration of cyclic adenosine monophosphate. These results indicate that complement-induced platelet microparticle formation is influenced by one or more protein kinase(s) as well as by calmodulin, and suggest a role for the platelet myosin light chain kinase or another Ca(2+)-pluscalmodulin-regulated membrane component.     

Acute respiratory distress syndrome of the adult

In a 43-year-old female patient after a bland influenzal infection suddenly an acute life-threatening picture of a disease with severe dyspnoea developed. Radiologically a distinct interstitial oedema was to be seen. According to the clinical and paraclinical data the case in question was the benign for of an acute dyspnoea syndrome of the adult. Etiology and therapy of the acute dyspnoea syndrome are shown. This picture of a disease should be included into the differential-diagnostic consideration in acute conditions of dyspnoea.     

Total respiratory pressure-volume curves in the adult respiratory distress syndrome

To assess the value of measuring compliance in the adult respiratory distress syndrome, sequential pressure-volume curves were obtained in 19 patients with this syndrome. Analysis of the pressure-volume curves allowed separation of the patients into the following four groups: (1) group 1 (n = 6), normal compliance measured during deflation, little hysteresis, and no inflection in the ascending limb of the pressure-volume tracing; (2) group 2 (n = 8), normal compliance during deflation, increased hysteresis, and presence of an inflection; (3) group 3 (n = 10), decreased compliance during deflation, marked hysteresis, and presence of an inflection; and (4) group 4 (n = 10), reduced compliance during deflation, no increased hysteresis, and no inflection. These patterns were correlated with the stage of the adult respiratory distress syndrome and to the pattern of the chest x-ray film. Group 2 corresponds to the initial stage of the syndrome and to pure alveolar opacities on the chest x-ray film. Group 3 is seen later in the course of the syndrome and corresponds to mixed alveolar and interstitial opacities. Group 4 corresponds to patients with end-stage adult respiratory distress syndrome (two weeks) and a predominant interstitial pattern on the chest x-ray film. Group 1 corresponds to a nearly normal chest x-ray film and to recovery.     

Hepatic dysfunction in the adult respiratory distress syndrome

Multiple organ system failure is a major cause of mortality in the adult respiratory distress syndrome (ARDS). We serially evaluated parameters of multiple organ function in 24 patients during the first week after the diagnosis of ARDS and related them to outcome. The adult respiratory distress syndrome was associated with sepsis (n = 16), postoperation (n = 7), and trauma (n = 1). Fourteen of the 24 patients (58 percent) died. Although there were no significant differences in the indices of pulmonary or renal dysfunction between survivors and nonsurvivors, evidence of hepatic dysfunction was different in the two groups. On the day we identified ARDS, serum bilirubin was 1.2 mg/dl +/- 0.9 mg/dl in patients who survived, and was 2.3 mg/dl +/- 2.8 mg/dl (chi +/- SD) in those who died. Initial serum glutamic oxalacetic transaminase (SGOT) and alkaline phosphatase levels were lower in survivors than in those who died (71 +/- 44 IU/L vs 399 +/- 807 IU/L, and 121 +/- 53 IU/L vs 269 +/- 243 IU/L, respectively). These abnormalities persisted during the first week of respiratory failure, with significant differences in serum bilirubin and alkaline phosphatase between survivors and nonsurvivors (p less than 0.01). The degree of pulmonary and renal dysfunction was similar in both groups. These data suggest that liver function may be a major determinant of survival in patients with the adult respiratory distress syndrome.