Gut as a possible source for endotoxemia.
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Animals↗
Biomedical subjects
S Bahrami
Publications and source records attributed to S Bahrami.
Monoclonal antibody to endotoxin attenuates hemorrhage-induced lung injury and mortality in rats.
OBJECTIVES: To determine the possible role of enteric bacteria-derived endotoxin in the pathogenesis of the lung injury and mortality in rats following hemorrhagic shock and resuscitation. DESIGN: Prospective, randomized study. SETTING: Animal laboratory of an institute for research traumatology. SUBJECTS: Male Sprague-Dawley rats, weighing 450 to 480 g. INTERVENTIONS: Anesthetized rats were subjected to a prolonged hemorrhagic shock (mean arterial pressure of 30 to 35 mm Hg for 180 mins) followed by resuscitation. A murine monoclonal antibody to lipopolysaccharide from Escherichia coli and Salmonella, WN1 222-5, was administered at a total dose of 5 mg/kg i.v., starting at the onset of shock (WN1 group). The control group was treated similarly to the WN1 group but received saline at the same volume as WN1 222-5. MEASUREMENTS AND MAIN RESULTS: The 48-hr mortality rate was significantly reduced by WN1 222-5 treatment (28.6% in the treatment group vs. 78.6% in the control group; p = .0169). The characteristic lung injury in this model was significantly reduced in the WN1 group, as assessed by microscopic histopathologic examination increase in lung wet weight (7.60 +/- 0.47 g/kg in the control group vs. 5.14 +/- 0.31 g/kg in the WN1 group; p = .0002), and pulmonary neutrophilic infiltration (myeloperoxidase activity: 1835 +/- 567 mU/g wet weight in the control group vs. 891 +/- 212 mU/g wet weight in the WN1 group). CONCLUSIONS: These data suggest that a) endotoxin derived from enteric bacteria might play an important role in the pathogenesis of lung injury; and b) antiendotoxin agents, such as WN1 222-5, appear to protect against endogenous bacterial endotoxin-related disorders in severe hemorrhagic shock in rats.
Animals↗
Significance of TNF in hemorrhage-related hemodynamic alterations, organ injury, and mortality in rats.
To evaluate the role of tumor necrosis factor-alpha (TNF-alpha) in hemodynamic alterations, multiple organ damage, and mortality caused by hemorrhagic shock, we employed a monoclonal antibody to TNF-alpha (TNF-alpha MAb) in anesthetized rats subjected to prolonged hemorrhagic shock (mean arterial pressure of 30-35 mmHg for 180 min) followed by resuscitation over 50 min. Treatment of rats with 20.0 mg/kg TNF-alpha MAb 15 min after the end of resuscitation significantly decreased the total peripheral resistance index (P = 0.031) and provided remarkable protection from multiple organ damage compared with controls. The 48-h survival rate was significantly higher in the treatment group (73.3%) than in the control group (26.7%; P = 0.029). The results suggest that TNF-alpha induced by hemorrhagic shock in rats is an important mediator of pathophysiological alterations associated with cardiovascular abnormalities, multiple organ injury, and even lethality. Postresuscitation treatment with TNF-alpha MAb, even after an initial TNF-alpha formation had occurred, significantly attenuated the cardiovascular consequences and improved the survival rate. Thus monoclonal antibodies to TNF-alpha might provide new prospects in the treatment of hemorrhage-related disorders.
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[Effects of amniotic fluid embolism-like plasma on isolated perfused rabbit lungs].
OBJECTIVE: In order to investigate whether amniotic fluid could induce the release of mediators from blood cells which would damage the lungs, an isolated perfused rabbit lung (IPRL) was exposed to amniotic fluid embolism-like plasma (AFEP) and the injury of AFEP to lungs and the protective effects of ibuprofen were studied. METHODS: 10 ml human amniotic fluid and 50 ml heparized rabbit blood were incubated together with or without ibuprofen (600 micrograms) at 37 degrees C for 30 min and centrifuged. Supernatants were taken and were referred to as AFEP or ibuprofen AFEP. IPRL was perfused with AFEP, ibuprofen AFEP, simple amniotic fluid (SAF), supernatant of amniotic fluid (SnAF), rabbit plasma (RP) and control NS. The changes of pulmonary artery pressure (PAP), respiratory pressure (RP) and lung weight were recorded by computer and compared with control NS group. RESULTS: In groups of SAF, SnAF and RP PAPs were slightly elevated (0.13-0.6 kPa, P > 0.05), and lung weights were not changed. AFEP induced the increase of PAP (3.52 +/- 0.64 kPa, P < 0.05) and lung weight (4.0 +/- 1.0 g, P < 0.01) with the development of lung edema. Administration of ibuprofen prevented partially the APEP-induced increase of PAP (1.87 +/- 0.43 kPa, P < 0.05) and lung weight (0.4 +/- 0.3 g, P < 0.01). CONCLUSION: Amniotic fluid may induce the release of mediators from blood cells, and the latter is the important cause resulting in the pathological changes of lungs in amniotic fluid embolism. Ibuprofen may reduce partially the APEP-induced lung injury.
Animals↗
Involvement of bacteria/endotoxin translocation in the development of multiple organ failure.
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Animals↗
Attenuation of shock-induced inflammation in the rat liver depends on the time of TNF-alpha inhibition.
The relevance of tumor necrosis factor-alpha (TNF-alpha) inducing early inflammatory reactions in the liver after hemorrhagic shock, for example, leukocyte adhesion, has been well described. This study evaluated the anti-inflammatory effects of a monoclonal antibody against TNF-alpha (TN3.19.12) in terms of the time of application, namely, prior to shock induction, at the time of resuscitation, and after resuscitation. The hepatic microcirculation was investigated by intravital fluorescence microscopy in female Sprague-Dawley rats undergoing severe hemorrhagic shock for 60 min and subsequent resuscitation. TN3.19.12 or placebo was given in a randomized and blinded manner either 60 min prior to shock induction, 1 min prior to resuscitation, or 15 min after the onset of resuscitation. The number of firmly adherent leukocytes in the livers of treated animals depended on the time of application of TN3.19.12. Leukocyte adhesion was significantly reduced when TN3.19.12 was given prior to shock induction or at the time of resuscitation and was less effective when administered after the onset of resuscitation. The results further confirm that TNF-alpha initiates very early pathological leukocyte adhesion in the liver 5 h following shock. Inhibition of leukocyte adhesion after shock, however, depends strongly on the time of TNF-alpha blocking. While TN3.19.12 prior to shock induction resulted in most effective attenuation, only very early treatment allowed limitation of posttraumatically increased leukocyte adhesion.
Animals↗
Animal models as the basis of pharmacologic intervention in trauma and sepsis patients.
With limited resources and the current concerns about using animals for research purposes, the needs must be clear when setting up trauma and sepsis experiments for pharmacologic interventions. Such interventions are performed typically for four reasons: (1) to study the pathophysiologic role of certain mediators (which can be influenced by pharmacologic agents); (2) to study the therapeutic efficacy of treatment strategies; (3) to study the overall safety of new drugs under trauma/sepsis conditions, which are adjunct studies to standard toxicology; (4) to test new diagnostic procedures in a defined trauma or sepsis setting. Intervention in the inflammatory response may be performed at several levels: (1) at the primary induction site (e.g., by antilipopolysaccharide or by preventing complement activation); (2) at the intermediate mediator level (e.g., by antitumor necrosis factor); (3) at the final mediator level (e.g. , by block of polymorphonuclear neutrophil elastase, and (4) at the target (e.g., by membrane stabilization or enhanced antioxidant defense).
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Systemic inflammatory response syndrome after cardiac operations.
BACKGROUND: A systemic inflammatory response after open heart operation may be responsible for hyperdynamic circulatory instability and organ dysfunction. To what extent mediator release is involved needs to be clarified. METHODS: Ten patients with postoperative hyperdynamic circulatory dysregulation (group I) requiring application of alpha-constrictors and 10 patients with routine cardiac procedures and stable postoperative hemodynamic indices (group II) were analyzed for mediator release and metabolic and hemodynamic changes until the third postoperative day. RESULTS: Group I patients showed a significantly increased cardiac index and decreased systemic vascular resistance after bypass (cardiac index, group I: 5.2 +/- 1.2 L.min-1.m-2, group II: 2.5 +/- 1.6 L.min-1.m-2; systemic vascular resistance, group I: 495 +/- 204 dyne.s. cm-5, group II: 1,356 +/- 466 dyne.s.cm-5) and at 3 hours (cardiac index, group I: 4.4 +/- 0.8 L.min-1.m-2, group II: 2.9 +/- 0.6 L.min-1.m-2; systemic vascular resistance, group I: 567 +/- 211 dyne.s.cm-5, group II: 1,053 +/- 273 dyne.s.cm-5). Significantly higher serum levels of interleukin-6 were assessed in group I (postbypass, group I: 6,812 +/- 9,293 pg/mL, group II: 295 +/- 303 pg/mL; 3 hours, group I: 3,474 +/- 5,594 pg/mL, group II: 286 +/- 296 pg/mL). Concentrations of elastase, tumor necrosis factor, soluble tumor necrosis factor receptor, and interleukin-8 were elevated in group I (not significant). Early postoperative levels of soluble E-selectin and soluble intercellular adhesion molecule were also higher in group I (not significant). Continuously increased levels of endotoxin could be detected in only 3 of 10 patients in group I. Severe lactic acidosis (> or = 5 mmol/L) occurred in group I only. CONCLUSIONS: Postoperative hyperdynamic instability after open heart operations appears to be associated with a certain pattern of mediator release. In particular, interleukin-6 appears to be involved in circulatory dysregulation and metabolic derangement.
Acidosis, Lactic↗
Comparison of endothelial activation during endotoxic and posttraumatic conditions by serum analysis of soluble E-selectin in nonhuman primates.
Because the presence of E-selectin, which is one of the adhesion molecules on the endothelium, cannot be determined directly in vivo except by invasive biopsy techniques, the only available kinetic information concerning its activity is the serum level of the soluble form. Therefore we tried to measure soluble E-selectin levels and compare the degree of endothelial activation in a trauma and endotoxic situation, where endothelial activation is supposed to occur. To perform these studies, an enzyme-linked immunosorbent assay with two monoclonal antibodies was set up and used in (1) a model of endotoxic shock in baboons (n = 8) (1.5 mg/kg Escherichia coli endotoxin as a 10-minute intravenous infusion), (2) a hemorrhagic traumatic shock model in baboons (n = 6), where trauma was simulated by infusion of zymosan-activated serum and hemorrhage. Soluble E-selectin was released in vivo after the application of endotoxin, and it reached a peak level after 24 hours (13.82 +/- 5.38 ng/ml). In baboons with hemorrhagic shock, much lower levels (5.03 +/- 1.98 ng/ml) of soluble E-selectin were found. A lower soluble E-selectin level indicates a lower level of endothelial activation after experimental hemorrhagic traumatic shock (with endotoxin translocation from the gut) as compared with endotoxic shock probably caused by much lower endotoxin levels in traumatic shock.
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Evaluation of a soluble E-selectin enzyme-linked immunosorbent assay under posttraumatic conditions.
The up-regulation of E-selectin, one of the adhesion molecules on the endothelium, is an important event in the mediation of the inflammatory response. Because the presence of E-selectin cannot be determined directly in vivo except by invasive biopsy techniques, the only available information concerning its activity is the serum level of the soluble form. Therefore we tried to measure soluble E-selectin levels in trauma and sepsis situations, where endothelial activation is supposed to occur. We have investigated the soluble E-selectin levels in a group of patients undergoing the trauma associated with cardiac surgery and the use of extracorporeal circulation, some of whom developed a systemic inflammatory response syndrome (SIRS). We have also confirmed that our enzyme-linked immunosorbent assay (ELISA) will detect the levels of soluble E-selectin that are produced as a result of the exposure of cultured human umbilical endothelial cells to even low levels of endotoxin. The data presented in this paper indicate that in patients with SIRS after extracorporeal circulation, the levels of circulating soluble E-selectin are numerically higher but---at least in this group of patients---not statistically significantly different from the levels in patients who have undergone the surgery. These results suggest that the measurement of serum levels of soluble E-selectin is not a reliable method for monitoring the onset of SIRS in patients having undergone surgical trauma, although we have confirmed that our ELISA will detect the levels of soluble E-selectin that are produced as a result of the exposure of cultured human endothelial cells to even low levels of endotoxin.
Adult↗
Differential effects of parathyroid hormone fragments on collagen gene expression in chondrocytes.
The effect of parathyroid hormone (PTH) in vivo after secretion by the parathyroid gland is mediated by bioactive fragments of the molecule. To elucidate their possible role in the regulation of cartilage matrix metabolism, the influence of the amino-terminal (NH2-terminal), the central, and the carboxyl-terminal (COOH-terminal) portion of the PTH on collagen gene expression was studied in a serum free cell culture system of fetal bovine and human chondrocytes. Expression of alpha1 (I), alpha1 (II), alpha1 (III), and alpha1 (X) mRNA was investigated by in situ hybridization and quantified by Northern blot analysis. NH2-terminal and mid-regional fragments containing a core sequence between amino acid residues 28-34 of PTH induced a significant rise in alpha1 (II) mRNA in proliferating chondrocytes. In addition, the COOH-terminal portion (aa 52-84) of the PTH molecule was shown to exert a stimulatory effect on alpha1 (II) and alpha1 (X) mRNA expression in chondrocytes from the hypertrophic zone of bovine epiphyseal cartilage. PTH peptides harboring either the functional domain in the central or COOH-terminal region of PTH can induce cAMP independent Ca2+ signaling in different subsets of chondrocytes as assessed by microfluorometry of Fura-2/AM loaded cells. These results support the hypothesis that different hormonal effects of PTH on cartilage matrix metabolism are exerted by distinct effector domains and depend on the differentiation stage of the target cell.
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Monoclonal antibody to tumor necrosis factor-alpha attenuates hemodynamic dysfunction secondary to intestinal ischemia/reperfusion in rats.
OBJECTIVE: To evaluate the effects of monoclonal antibody to tumor necrosis factor (TNF)-alpha on the hemodynamic alterations and survival rate in rats subjected to intestinal ischemia/reperfusion. DESIGN: Prospective, randomized study. SETTING: Animal laboratory of an institute for research in traumatology. SUBJECTS: Male Sprague-Dawley rats, weighing 430 to 460 g. INTERVENTIONS: Anesthetized rats underwent 75 mins of superior mesenteric artery occlusion followed by 6 hrs of reperfusion. The animals were treated intravenously with either TNF-alpha monoclonal antibody (TN3, 20 mg/kg) or the control protein (albumin, 20 mg/kg) 30 mins before the onset of ischemia. MEASUREMENTS AND MAIN RESULTS: Pretreatment with TNF-alpha monoclonal antibody significantly attenuated the decreases in blood pressure and cardiac index (p < .01) compared with controls, for < or = 6 hrs after reperfusion. Stroke volume remained stable in the TNF-alpha monoclonal antibody-treated group and was significantly higher than in the control group at 0.5, 5, and 6 hrs after reperfusion (p < .05 at 0.5 and 5 hrs and p < .01 at 6 hrs). No differences in vascular resistance index values were observed between the two groups at any point in time (p > .05). After intestinal ischemia/reperfusion injury, both the portal and systemic TNF concentrations in the control animals were completely neutralized by TNF-alpha monoclonal antibody treatment. The 72-hr survival rate was significantly (p < .01) better in the treatment group (90%, 9/10) than in the control group (20%, 2/10). CONCLUSIONS: These results suggest that intestinal ischemia/reperfusion injury can lead to increased TNF release into both the portal and the systemic circulation, which may be an important factor contributing to the development of hemodynamic dysfunction. Pretreatment with TNF-alpha monoclonal antibody significantly attenuates the cardiovascular consequences and improves the survival rate after acute intestinal ischemia/reperfusion injury.
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Comparison of the efficacy of pentoxifylline and albifyllin (HWA 138) on endotoxin-induced cytokine production, coagulation disturbances, and mortality.
We have evaluated two different xanthine derivatives, pentoxifylline (POF) and albifyllin (HWA), in rat endotoxemia for their ability to reduce 1) cytokine formation, 2) coagulation disturbances, and 3) mortality. The animals were injected with lipopolysaccharide (LPS) (15 mg/kg i.p.) and received HWA or POF (25, 50, or 100 mg/kg) or saline 30 min before LPS administration. The plasma tumor necrosis factor levels were significantly reduced and in a similar manner by pretreatment with HWA or POF in vivo as well as in vitro. Neither the coagulation disturbance nor the characteristic leukopenia that follow an LPS challenge were significantly influenced by the xanthine derivatives. At a dose of 100 mg/kg, the 6 day mortality was significantly reduced by HWA to 36% but only attenuated by POF to 55% as compared to 80% in the control group. The similar effect of both agents on cytokine formation and coagulation disturbances indicate that, at least to a substantial degree, other mechanisms may account for the significant protection of rats against endotoxin-induced mortality by HWA only. HWA 138 may, therefore, be a new powerful agent against endotoxin-related disorders and mortality.
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Significance of NO in hemorrhage-induced hemodynamic alterations, organ injury, and mortality in rats.
In an attempt to evaluate the role of nitric oxide (NO) in pathophysiological alterations and multiple organ damage caused by hemorrhagic shock, we employed NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, in anesthetized rats subjected to a prolonged hypovolemic insult (30-35 mmHg for 180 min). Infusion of 2.0 mg/kg L-NMMA at the end of resuscitation diminished the fall in mean arterial pressure (MAP) and significantly increased the cardiac index and stroke volume, together with remarkable protection from multiple organ damage compared with the controls. The 48-h survival rate was significantly improved from 26.7% in the control group to 68.8% in the treatment group (P < 0.05). In contrast, the high dose of 20.0 mg/kg L-NMMA resulted in a strong blood pressure response, but a marked reduction in cardiac index and stroke volume concomitant with an increased total peripheral resistance index within the observation period, and tended to increase damage to various organs at 2 h after treatment. In addition, marked elevation in both endotoxin and tumor necrosis factor levels were observed in animals subjected to shock insult. The results suggest that NO induced by hemorrhagic shock in rats is an important mediator for pathophysiological alterations associated with cardiovascular abnormalities, multiple organ dysfunction, and even lethality. Regulation of NO generation and use of NO inhibitors might provide new aspects in the treatment of hemorrhage-related disorders, whereas the administration of L-NMMA would be either deleterious or salutary in a dose-dependent manner.
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Endogenous modulators of TNF and IL-1 response are under partial control of TNF in baboon bacteremia.
Tumor necrosis factor (TNF) and interleukin (IL)-1 are two cytokines for which naturally occurring inhibitors have been identified. The present study was undertaken to evaluate the extent to which scavenging of TNF in bacteremia attenuates the plasma levels of IL-1 receptor antagonist (IL-1ra) and soluble TNF receptors (sTNFR). Ten male baboons received 2 x 10(9) colony-forming units/kg live Escherichia coli over 2 h and were subjected to either placebo or anti-TNF antibody (anti-TNF Ab) treatment (1 mg/kg CDP571, Celltech, UK) 2 h before E. coli infusion (observation time: 72h). IL-1ra (range: 50-100 ng/ml) and sTNFR (range: 55kDa, 20-25 ng/ml; 75 kDa, 30-35 ng/ml) release was more sustained than that of IL-1 and TNF and was significantly attenuated by anti-TNF treatment, as were the circulating levels of IL-1, IL-8, and monocyte chemotactic peptide-1 (MCP-1) in the anti-TNF Ab group. We conclude that the increase in circulating natural cytokine modulators observed in nonhuman primate bacteremia is under the partial control of endogenous TNF because it was influenced by anti-TNF pretreatment. This attenuation is comparable to the anti-TNF effect on the chemokine MCP-1.
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Kinetics of endotoxin and tumor necrosis factor appearance in portal and systemic circulation after hemorrhagic shock in rats.
OBJECTIVE: This study was performed to investigate gut-derived bacterial translocation and the time course of endotoxin (lipopolysaccharide [LPS]) and tumor necrosis factor (TNF) appearance, both in portal and systemic circulation. SUMMARY BACKGROUND DATA: The significance of intestinal bacteria/endotoxin translocation or TNF formation in the development of systemic sepsis has been disputed. METHODS: A rat model of hemorrhagic shock (30-35 mm Hg for 90 min) and resuscitation was used. RESULTS: Bacterial translocation was histologically observed in the small intestinal wall 30 minutes after resuscitation. A significant increase in LPS concentrations was found in the portal vein (91.7 +/- 30.6 pg/mL) at 90 minutes, which remained steady until 150 minutes after shock. Lipopolysaccharide increased in the systemic circulation, the levels became significant at 120 minutes, and peaked (66.5 +/- 39.2 pg/mL) 150 minutes after shock. Tumor necrosis factor concentrations were found to be significantly elevated in both portal and systemic circulation (75.6 +/- 22.1 vs. 58.4 +/- 14.1 pg/mL) at 90 minutes post-shock. Although there was no further increase in TNF concentration in the portal blood. TNF peaked (83.5 +/- 17.7 pg/mL) in systemic circulation at 120 minutes and still was markedly increased at 150 minutes post-shock. In addition, higher LPS and TNF concentrations in systemic circulation were found in the nonsurvivors than in the surviving animals at the end of resuscitation. CONCLUSIONS: These results suggest that hemorrhagic shock may lead to early bacterial translocation in the intestinal wall and transient access of gut-derived LPS and LPS-induced mediators into the circulation predominantly via the portal circulation.
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Pathogenesis of hemorrhage-induced bacteria/endotoxin translocation in rats. Effects of recombinant bactericidal/permeability-increasing protein.
OBJECTIVES: This study was conducted to determine the role of gut-derived bacteria/endotoxin in the pathogenesis of the multiple-organ damage and mortality, the possible beneficial effect of recombinant bactericidal/permeability-increasing protein (rBPl21), and whether neutralizing endotoxemia by rBPl21 treatment influences tumor necrosis factor (TNF) formation in rats after hemorrhagic shock and resuscitation. SUMMARY BACKGROUND DATA: Hypovolemic shock might be associated with bacterial or endotoxin translocation as well as systemic sepsis. Similar to bactericidal/permeability-increasing (BPl) protein, rBPl21 has been found to bind endotoxin and inhibit TNF production. METHODS: A rat model of prolonged hemorrhagic shock (30 to 35 mm Hg for 180 min) followed by adequate resuscitation was employed. Recombinant bactericidal/permeability-increasing protein was administered at 5 mg/kg intravenously. The control group was treated similarly to the BPl group, but received thaumatin as a protein-control preparation in the same dose as rBPl21. RESULTS: Immediately after resuscitation (230 min), plasma endotoxin levels in the control group (61.0 +/- 16.3 pg/mL) were almost neutralized by rBPl21 treatment (13.8 +/- 4.8 pg/mL, p < 0.05). Plasma TNF levels were not significantly influenced by rBPl21 treatment. The 48-hour survival rate was 68.8% in the treatment group versus 37.5% in the control group (p = 0.08). Microscopic histopathologic examination revealed relatively minor damage to various organs in the treatment group. CONCLUSIONS: These data suggest that hemorrhagic shock may lead to bacterial/endotoxin translocation with concomitant TNF formation, endogenous endotoxemia may play an important role in the pathogenesis of multiple-organ failure after shock and trauma, TNF formation at an early stage might be related mainly to mechanisms other than Kupffer's cells activation via lipopolysaccharide, and rBPl21 might be a useful therapeutic agent against endogenous bacteria/endotoxin related disorders in severe hemorrhagic shock.
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Acute lung injury by endotoxin-induced mediators: prevention by HWA 138, a new xanthine derivative.
We attempted to mimic septic conditions in vitro by using a model of isolated perfused rabbit lung (IPRL) and evaluated the effects of endotoxin or endotoxin-induced mediators (or both) on it. Moreover, we determined the salutary effects of HWA 138, a new xanthine derivative, against endotoxin-related lung injury. To study this, heparinized human blood was centrifuged, following which the plasma complement was inactivated by heat treatment and the isolated and washed buffy coat cells were then added to it. This was followed by incubation of aliquot suspension with and without endotoxin (lipopolysaccharide [LPS], 100 ng/ml) at 37 degrees C for 2 hours. Plasma was then harvested and is referred to as sepsis-like plasma (SLP). Control plasma (CP) was not exposed to LPS. IPRLs were then perfused with SLP, CP, LPS itself, or both LPS and CP without additional white blood cells. Endotoxin itself did not induce any changes in the presence or in the absence of control plasma; however, sepsis-like plasma led to the development of lung edema, as evidenced by significantly elevated lung water and pulmonary artery pressure. Administration of HWA 138 before the addition of SLP prevented the SLP-induced lung injury. These results lead us to conclude that lung injury is caused by LPS-induced mediators rather than being directly caused by LPS. The results also suggest that HWA 138 may be a useful agent in the treatment of sepsis-induced pulmonary injury.
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