摘要:

Injury to the vascular endothelium is a critical event in acute inflammatory disease processes. In acute inflammation, endothelial cell injury is frequently mediated by activated neutrophils. The process by which activated neutrophils produce endothelial cell damage is complex. It involves generation of reactive oxygen metabolites, principally hydrogen peroxide (H202), and reduction of the H2O2 to the hydroxyl radical within the target cell. Hydroxyl radical generation depends on a source of superoxide anion and iron, and it appears that the target cell is the source of both. Thus, the endothelial cell actively participates in the biochemical events that lead to the formation of the toxic radical. Although neutrophil oxidants play a major role in injury, other neutrophil products, released from granules during activation, also contribute to injury. In addition to neutrophil products, other moieties present at inflammatory sites, including tumor necrosis factor-α and interleukin-1 can also participate in injury of endothelial cells. The cytokines may be directly injurious to endothelial cells under some conditions and may potentiate neutrophil-mediated injury under others. Like injury resulting from activated neutrophils, cytokine-induced endothelial cell injury also appears to involve generation of reactive oxygen metabolites within the target cells. Finally, endothelial cells become susceptible to injury as they age in vitro. The mechanism by which spontaneous injury occurs in aging cells appears to be significantly different from that responsible for neutrophil-induced and cytokine-induce injury. Age-related injury resembles apoptosis in a number of respects.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We previously reported that sequential exposure of cultured porcine aortic endothelial cells to lipopolysaccharide (LPS) and then to inducers of the heat shock response resulted in lethal injury by programmed cell death. In these present experiments, we evaluated the ability of other mediators of sepsis to prime endothelial cells for subsequent injury upon heat shock induction. We used SVEC4–10 microvas-cular endothelial cells, a cloned SV40-transformed cell line derived from LPS-resistant C3H/HeJ mice. When these endothelial cells were treated first with tumor necrosis factor-α followed by induction of the heat shock response with either heat or sodium arsenite (As), a standard chemical inducer of the heat shock response in vitro, a tumor necrosis factor dose-dependent cytotoxicity was observed, similar to that which we had seen previously in porcine endothelial cells primed with LPS. Subsequent experiments found that priming with interferon-α produced a similar dose-dependent toxicity upon heat shock with either heat or As. The reducing agents dithiothreitol and n-acetylcysteine, which we have previously shown to inhibit heat shock-induced programmed cell death in LPS-primed porcine endothelial cells, were also effective in protecting against heat shock-induced death following cytokine-priming in this microvascular cell line, suggesting that the intracellular signaling pathways of these priming agents are somewhere convergent. These data suggest that both exogenous and endogenous mediators of inflammation can prime endothelial cells for subsequent injury upon induction of the heat shock response, and are consistent with the emerging concept of redundancy in inflammatory signaling.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Endotoxin (lipopolysaccharide, LPS) can induce shock, multiple organ failure, and death. A recombinant N-terminal fragment of bactericidal/permeability increasing protein, rBPI23, binds with high affinity to gram-negative bacterial LPS and neutralizes its biological activity. We sought to determine the effect of rBPI23 on LPS-induced respiratory dysfunction and cardiovascular depression in conscious rabbits. Rabbits were injected with Escherichia coli 0113 LPS (6 μg/kg) and treated with rBPI23 (2 mg/kg), vehicle, or control protein after recovery from surgery performed to implant catheters for hemodynamic assessments and intravenous injections. LPS challenge caused respiratory dysfunction including tachy-pnea, significant decreases in arterial 02 tension (Po2), arterial oxygen content, and an increase in alveolar-arterial 02 gradient (A-aDo2). LPS administration also resulted in profound and prolonged decreases in mean arterial blood pressure and cardiac index. Treatment with rBPI23 prevented LPS-induced respiratory dysfunction and significantly ameliorated the cardiovascular depression. 5 of 16 LPS-chal-lenged animals died of respiratory failure and acidosis, whereas none died in the rBPI23 treated group (p = .11). The results demonstrate that rBPI23 protects animals against LPS-induced cardiopulmonary depression in endotoxic shock.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

To further clarify the mechanism of polymorphonuclear leukocyte (PMN) recruitment into the liver associated with short term endotoxin infusion (1), we investigated the effect of a novel factor generated by hepatocytes of such endotoxic rats on the expression of PMN adhesion molecules CD11b/c and chemotactic activity. Conditioned medium of hepatocytes from endotoxin-infused rats shows a fast induction and dose-dependent activity for upregulating CD11 b/c expression in and chemotactic activity for blood PMN of naive rats. Supernatants of naive control rats cultured in the presence of endotoxin and Kupffer cells and liver PMNs of endotoxic rats also produce activation, but to a much lesser extent. The upregulating activity can be reduced significantly by heat inactivation at 100°C for 10 min and by pronase hydrolysis at 37°C for 60 min. Generation of the activity does not depend on cyclooxygenase products or phospholipase A2 activity, and it does not seem to be associated with the complement pathway. The activity is associated with molecular masses of 9–12 and 27–32 kDa and cannot be reduced by antiserum to rat interleukin-8 in serial dilutions ranging from 1:50 to 1:25,600. The results show that hepatocytes from acutely endotoxin infused rats generate a small molecular weight protein factor (or factors) that is capable of upregulating PMN 11b/c expression and chemotactic activity and is seemingly different from rat interleukin-8. Thus, hepatocytes in endotoxemia may play an important role in modulating neutrophil function and contributing to the mechanism of neutrophil sequestration into the liver.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The effect of infection on gluconeogenesis was assessed in the chronically catheterized conscious dog. Dogs were studied 42 h after implantation of a sterile (n = 7) or an Escherichia coli containing (n = 7) fibrinogen clot into the peritoneum (54 h fasted). Infection increased arterial plasma glucagon and cortisol (4.2− and 2.1-fold, respectively), but it did not alter arterial plasma insulin, cat-echolamines, or glucose concentrations. Infection increased tracer ([3–3H]glucose) determined glucose production and utilization and net hepatic glucose output by 35%. Net hepatic alanine and lactate uptake were also increased by 34 and 54%, respectively, without an alteration in their net hepatic fractional extraction. The intrahepatic efficiency of conversion of [14C]alanine to [14C]glucose was not decreased in the septic dog (.77 ± .08) vs. .95 ± .10 in noninfected and infected, respectively). Intestinal glucose uptake and lactate release were increased approximately twofold. The increase in intestinal lactate release accounted for 35% of the increase in net hepatic lactate delivery seen in response to infection. In conclusion, a good model of hypermetabolic infection was developed in which the characteristic increases in hepatic glucose production and gluconeogenesis were observed in the fasted state. The increase in gluconeogenesis was due to an increase in hepatic gluconeogenic precursor uptake with no impairment in the net fractional hepatic extraction of gluconeogenic precursors or the efficiency of gluconeogenesis. In addition, the intestine is a significant contributor to the increase in gluconeogenic precursor supply seen in response to infection.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We tested the hypothesis that Starling resistor forces play a significant role in the increase in pulmonary vascular resistance during endotoxin shock. Anesthetized pigs (n = 9) were given Escherichia coli endotoxin (ETX; .5 mg/kg intravenously over 30 min). Mean pulmonary arterial pressure (MPAP) and pulmonary capillary wedge pressure (PCWP) were recorded through a Swan-Ganz catheter. Pulmonary capillary pressure (Pc) was obtained from the analysis of the transient pulmonary artery pressure decay curve upon balloon inflation. Both proximal (Ra) and distal (Rv) pulmonary vascular resistance were calculated from cardiac output (CO), MPAP, Pc, and PCWP. Left atrial pressure (LAP) was measured directly via a left atrial catheter. Left ventricular end-diastolic wall thickness (LV-EDWT) was monitored by sonomicrometry, and used as an index of left ventricular preload. The results at baseline (t = 0) and f = 60 (30 min after the cessation of endotoxin infusion) were compared with saline control animals (n = 6). Data were analyzed with a two-way ANOVA followed by contrast of residuals (p ± .05). After endotoxin, arterial blood pressure and CO fell significantly, an effect not seen in control pigs. In the control group neither LAP nor PCWP changed significantly over time, and remained equivalent to each other. In the septic shock group there was no difference between LAP and PCWP at t = 0. However, by t = 60 LAP dropped and PCWP rose significantly. This fall in LAP and increase in PCWP were significantly different from the time-matched control values, and from each other. The fall in LAP indicated a decreased left ventricular preload, which was validated by a significant increase in LV-EDWT at t = 60. Arterial Po2 fell after endotoxin administration, while Pco2 remained the same. In the control pigs total pulmonary resistance remained unchanged throughout the experiment, with Ra accounting for most of the pulmonary vascular resistance. In the septic shock group, increases in both Ra (158%) and Rv (706%) accounted for an increase in total pulmonary vascular resistance. The dissociation of PCWP from LAP concomitant with significant increases in Rv after endotoxin is consistent with Starling resistor forces exerting a significant influence on Rv during endotoxin shock. These data indicate that pulmonary hypertension after a septic insult cannot be attributed to venoconstriction alone. The inaccuracy of PCWP as an index of left heart filling pressure after endotoxin suggests that this parameter should be viewed cautiously in sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Liver injury is common in patients following hemorrhage and sepsis. There are multiple etiologies for this liver injury which involve both decreased nutrient blood flow and direct cellular injury. Enteral nutrients vasodilate gut blood vessels and increase blood flow to the intestines and liver. Since enteral nutrients vasodilate gut blood vessels, we wondered whether luminal nutrition would prevent hepatic injury during shock states. We randomized Sprague-Dawley rats to saline or enteral nutrition via duodenal feeding tubes. Animals were then subjected to 60 min of hemorrhagic hypotension or intra-peritoneal injection of lipopolysaccharide (LPS). Liver injury was assessed by measuring levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) before and after hemorrhage or LPS. Enteral nutrients significantly decreased liver injury following hemorrhage. AST increased from 246 ± 17 to 1605 ± 593 U/L in saline animals and 283 ± 39 to 551 ± 94 U/L in enterally fed animals. ALT increased from 60 ± 4 to 726 ± 355 U/L in saline animals and 61 ± 6 to 161 ±38 U/L in enterally fed animals. Enteral nutrients did not significantly alter the increase in AST/ALT following LPS. These results indicate that enteral nutrients can decrease liver injury following hemorrhagic hypotension.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Redistribution of fluid after isotonic crystalloid resuscitation from hemorrhage may result not only in interstitial edema but also in cellular edema. We measured the extent to which shock and resuscitation altered fluid compartments in different organs. Nephrectomized, anesthetized rats were randomly divided into a Control group (n = 10) and a Hemorrhage plus Resuscitation group (H/R, n = 10). Rats were subjected to 60 min hemorrhagic hypotension (50 mmHg) followed by a 60 min resuscitation period with .9% NaCI infused as needed to maintain mean arterial pressure at 80% of baseline. A 2 h 51Cr-EDTA distribution space was used to estimate extracellular fluid volume (ECFV) and a 5 min 125l-albumin distribution space was used to measure plasma volume (PV). After euthanasia, total tissue water was measured by wet/dry weight analysis and interstitial fluid volume (ISFV) and cell water were calculated for selected organs. Resuscitation volume was two times the shed blood volume, but resulted in a PV equal to that of the Controls. There were no significant differences in whole animal ECFV or ISFV, although the mean values in the H/R group were greater than that of the Control group. The mean values for total tissue water for each tissue in the H/R group were larger than the respective means of the Control tissues but was significantly greater for only the heart (3639 ± 56 μL/g vs. 3493 ± 24 μL/g, mean ± S.E., p < .05). In all H/R tissues, mean values for ISFV were also larger; this difference was significant for only the liver and small intestines (744 ± 62 vs. 518 ± 29 μL/g and 1117 ± 155 vs. 706 ± 58 μL/g, respectively). Heart cell water was significantly larger in H/R than Controls (2900 ± 60 μL/g vs. 2738 ± 27 μL/g). These data suggest that resuscitation of hemorrhage using isotonic crystalloid normalizes overall PV and ECFV but also causes interstitial expansion in selected gut tissues and cellular edema in the heart.

ISSN:1073-2322    

出版商:OVID    

年代:1994

数据来源: OVID