摘要:

In a prospective randomized, double-blind, placebo-controlled clinical study, the safety and efficacy of the platelet-activating factor antagonist TCV-309 in the treatment of systemic inflammatory response syndrome was studied. In total 29 patients were treated with 1.0 mg/kg TCV-309 twice daily during 7 days or with placebo. Study parameters were as follows: adverse events, 28 and 56 day all cause mortality, multi-organ failure scores, and the inflammatory mediators tumor necrosis factor, interleukin 6, interleukin 8, and soluble E-selectin. There was no difference in number and severity of adverse events between TCV-309- and placebo-treated patients. Day 28 and day 56 mortality was similar in both groups (day 56: 7/12 TCV-309 vs. 9/16 placebo, NS). Pulmonary and hematological failure scores improved significantly in TCV-309-treated patients (p < .05). There was no difference in inflammatory mediator levels between TCV-309- and placebo-treated patients. Treatment with TCV-309 appears to be safe in patients with systemic inflammatory response syndrome and does improve organ failure significantly.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We examined the level of heat shock proteins (HSPs) present in umbilical cord vessels and placenta following delivery. A 10 cm segment of fresh umbilical cord was obtained immediately after delivery and a placental biopsy was obtained following the third stage of labor. Apgar scores, cord pHs, and pertinent histories were recorded. Tissues were prepared and analyzed for HSP mRNA by in situ hybridization, Western blot, and immunohistochemistry. Sixteen patients were studied. HSP72 mRNA was selectively expressed in the vascular smooth muscle in all cord arteries and veins. This correlated with marked expression of HSP72 protein in the vascular media. Both HSP72/73 mRNA and protein expression were noted diffusely in the placenta. HSP27 protein was highly expressed in umbilical cords with lower levels present in placentas. There were no correlations between method of delivery, gestational age, Apgar score, cord pH, or fetal outcome to the magnitude or distribution of the HSP response. This is the first demonstration of HSP expression in the human maternal-fetal circulation.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Post-ischemic hepatic injury is characterized by zonal heterogeneity of injury (central lobular necrosis), sinusoidal neutrophil accumulation, and injury generated by reactive oxygen metabolites. We evaluated the role of the heterogeneous distribution of hepatic xanthine oxidase in the generation of neutrophil accumulation and consequent hepatocellular injury in rats subjected to shock [controlled hemorrhagic hypotension (mean arterial pressure = 37.5 ± 2.5 mmHg for 120 min)], with or without subsequent resuscitation and hemodynamic stabilization, compared with sham-operated rats. Shock/ resuscitation produced striking neutrophil accumulation (assayed by esterase histochemistry) in the pericentral sinusoids, associated with centrolobular necrosis. This paralleled the pericentral distribution of xanthine oxidase (determined by histochemical assay of frozen sections) and its release from the liver into the circulation at resuscitation. Pretreatment with allopurinol inhibited hepatic xanthine oxidase activity, neutrophil accumulation, and pericentral hepatocyte necrosis in shock/resuscitation in rats. These findings suggest that reactive oxygen metabolites generated by heterogeneously distributed xanthine oxidase may contribute to the heterogeneity of hepatocellular injury in “ischemic hepatitis.”

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Recent studies suggest that sepsis stimulates mucosal polyamine and protein synthesis. It is not known in which cell type polyamine biosynthesis is increased during sepsis and if polyamines regulate mucosal protein synthesis. We examined the effect of sepsis in rats on polyamine biosynthesis in isolated jejunal enterocytes and measured mucosal protein synthesis following inhibition of ornithine decarboxylase (ODC) activity with difluoromethylornithine. ODC and S-adenosylmethionine decarboxylase (SAMDC) activities and putrescine concentrations were increased in isolated jejunal enterocytes 16 h after induction of sepsis by cecal ligation and puncture. Enterocyte spermidine and spermine levels were not influenced by sepsis. Mucosal ODC and SAMDC activities and polyamine levels were increased following treatment of rats with interleukin-1 but not tumor necrosis factor. Treatment of rats with difluoromethylornithine prevented the sepsis-induced increase in mucosal ODC activity, putrescine concentration, and protein synthesis rate. The results suggest that sepsis increases ODC and SAMDC activities and putrescine concentrations in enterocytes of the small intestine. This metabolic response to sepsis may be regulated by interleukin-1 although other mechanisms may also be involved. Increased mucosal protein synthesis during sepsis may at least in part be regulated by increased putrescine levels.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The influence of inhibiting the nitric oxide (NO) synthetase on tissue perfusion as indicated by tissue oxygen tensions was determined. Tissue oxygen probes were placed subcutaneously and on serosal and mucosal surfaces of colon of anesthetized adult rats. After a control period, the inhibitor of NO formation, NG- nitro-l-arginine methyl ester (l-NMMA), was given intravenously and followed 20 min later by infusion of substrate for NO synthetase, l-arginine. Mean arterial blood pressure (MAP), subcutaneous tissue oxygen tension (PSQO2), serosal tissue oxygen tension (PsO2), and mucosal tissue oxygen tension (PMO2) were simultaneously measured. Baseline values for the measured parameters were MAP =95 ±9 mmHg, PSQO2= 61Plusmn;7 mmHg, PSO2= 65 ±7 mmHg, and PM02=9±2 mmHg. The infusion of l-NMMA induced a significant increase in MAP to 123±7 mmHg (p <.001) and PSQO2to 72 ±7 mmHg (p <001). PSO2did not change significantly from baseline after l-NMMA infusion. A significant decrease in PMO2to 4±2 mmHg was noted after l-NMMA infusion (p <.001). The administration of L-arginine promptly returned all measured parameters to baseline levels within 10 min of infusion. A transmural PO2gradient exists across the colon with PMO2far lower than PSO2. PSQO2approximates PSO2at baseline and PSO2is not altered by inhibition of the NO synthetase. The 45% reduction in mucosal PO2after l-NMMA, which was reversed by L-arginine infusion, suggests that nitric oxide participates in splanchnic vasomotor control with a preferential effect in the mucosal vasculature. The observed decrease in mucosal PO2observed after inhibition of NO production is similar to the worsened hypoxia previously measured during hemorrhagic shock. Further work clarifying the local control mechanisms of gut tissue PO2can direct therapies to increase gut tissue oxygenation.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The effects of a 4 h intraportal infusion of Escherichia coli lipopolysaccharide (LPS, .21 iu,g/kg/effects of a 4 h intraportal infusion of Escherichia coli lipopolysaccharide (LPS, .21 iu,g/kg/min) on the release of tumor necrosis factor (TNF) by hepatic and nonhepatic splanchnic tissues was assessed in the chronically catheterized conscious dog (n=7) using arteriovenous difference techniques. TNF levels were measured using both a WEHI-164 cytotoxicity assay (WEHI) and a h-TNF-a EIA kit (ELISA; Biosource, Camarillo, CA). Using WEHI, arterial TNF levels increased from 10 ±6 pg/mL to a peak of 4667 ±1442 pg/mL -100 min after LPS and fell to 443 ±199 pg/mL by 240 min. Using ELISA, arterial TNF levels increased from 5 ±5 pg/mL to a peak of 12,234 ±2046 pg/mLat~ 100 min and fell to 3511 & plusmn;991 pg/mL by 240 min. WEHI could not be used to assess organ TNF release due to excessive assay variability. Based upon ELISA, net hepatic TNF output increased from undetectable release at basal to 23.0±10.7 ng/kg/min at 60 min and returned toward basal by 240 min (4.7 ±3.8 ng/kg/min). Net release of TNF by the nonhepatic splanchnic bed was not observed. One compartment analysis of the arterial TNF response indicated that net release of TNF by the liver accounted for the majority of the increase in the arterial TNF levels. In summary, after intraportal LPS infusion, it was determined that 1) both assays predict similar qualitative TNF response, while the quantitative response differs, 2) the liver is the major site of TNF production, and 3) the nonhepatic splanchnic bed is not a net producer of TNF. kg/min) on the release of tumor necrosis factor (TNF) by hepatic and nonhepatic splanchnic tissues was assessed in the chronically catheterized conscious dog (n =7) using arteriovenous difference techniques. TNF levels were measured using both a WEHI-164 cytotoxicity assay (WEHI) and a h-TNF-a EIA kit (ELISA; Biosource, Camarillo, CA). Using WEHI, arterial TNF levels increased from 10 ±6 pg/mL to a peak of 4667 ±1442 pg/mL -100 min after LPS and fell to 443 ±119pg/mL by 240 min. Using ELISA, arterial TNF levels increased from 5 ±5 pg/mL to a peak of 12,234 ±2046 pg/mLat~ 100 min and fell to 3511±991 pg/mL by 240 min. WEHI could not be used to assess organ TNF release due to excessive assay variability. Based upon ELISA, net hepatic TNF output increased from undetectable release at basal to 23.0 ±10.7 ng/kg/min at 60 min and returned toward basal by 240 min (4.7 ±3.8 ng/kg/min). Net release of TNF by the nonhepatic splanchnic bed was not observed. One compartment analysis of the arterial TNF response indicated that net release of TNF by the liver accounted for the majojgrity of the increase in the arterial TNF levels. In summary, after intraportal LPS infusion, it was determined that 1) both assays predict similar qualitative TNF response, while the quantitative response differs, 2) the liver is the major site of TNF production, and 3) the nonhepatic splanchnic bed is not a net producer of TNF.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The goal of this study was to assess whether serial measurements of regional veno-arterial PcoC2(VAPco2) and arteriovenous pH (AVpH) differences reflect the onset of tissue hypoxia in various organs during endotoxemia. In 12 anesthetized, mechanically ventilated dogs, ultrasonic flow probes were placed around superior mesenteric, renal, and femoral arteries to measure regional blood flow. The corresponding veins were cannulated for blood sampling. Oxygen uptake (VO2) was determined from exhaled gas analysis, and oxygen delivery (DO2) was calculated as the product of thermodilution cardiac output and arterial oxygen content. Six dogs served as controls, and six received Escherichia coli endotoxin. Cardiac tamponade was induced to reduce D02. Systemic, mesenteric, and femoral critical D02(DO2crit) were higher in the endotoxic than in the control group (systemic: 12.1 ± 2.2 vs. 7.9 ± 2.6 ml/kg-min; mesenteric: 8.2 ± 2.5 vs. 4.1 ± .6 ml/100 g tissue-min; femoral: 8.3 ± 2.3 vs. 4.6 ± .9 ml/min; all p<.05). Systemic and regional critical oxygen extraction ratio (O2ERcrit) were lower in the endotoxic than in the control group (systemic: 45.1 ±9.7vs.74.1 ± 9.1%; mesenteric: 37.1 ±15.4 vs. 71.1 ±7.4%; renal: 30.7 ± 24.6 vs. 53.9 ± 28.7%; femoral: 48.1 ± 9.2 vs. 75.3 ± 6.9%; all p<.05). With and without endotoxin, systemic and regional DO2crit calculated from VO2, VAPco2, or AVpH were similar. In conclusion, systemic and regional VAPco2and AVpH gradients can reflect hypoxic threshold in the presence, as in the absence, of endotoxemia.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

In vitro, endotoxin primes polymorphonuclear leukocytes (PMNs) to respond with a greateroxidative burst. The purpose of the present study was to investigate the In vivo effect of a wide range ofsingle endotoxin bolus doses using a rat model. PMNs were subsequently challenged In vitro with phorbolester to produce reactive oxygen intermediates (ROI). Flow cytometric determination of ROI production byPMNs using the dichlorofluorescin conversion assay showed that although low doses induced priming,large doses induced a decrease in ROI production by the few PMNs that remained in the circulation. By 6 hafter injection, ROI production had returned to basal levels after a high dose, and was still increasing aftera low dose. Neutropenia occurred immediately after endotoxin injection. After 6 h, PMN counts returned toalmost normal levels with a high dose, but rebound neutrophilia occurred with a small dose. In contrast toin vitro studies, in vivo injection showed a response pattern that varied widely with dose and time ofobservation.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Hypotension is a serious problem in septic patients. We investigated regional perfusion in several organs during treatment of hyperdynamic sepsis in sheep. Sepsis was induced and maintained for the entire experiment with a continuous infusion of live Pseudomonas aeruginosa. Treatment with either norepinephrine or the nitric oxide synthase inhibitor Lω-mono-methyl-arginine (l-NMMA) was begun after 24 h of sepsis and continued for 24 h. The norepinephrine dosage was adjusted to achieve the same increase in mean arterial pressure as that obtained by a fixed dose of l-NMMA (7 mg/kg/h). Blood flows were analyzed by the microsphere technique. Both compounds restored blood pressure effectively, but only L-NMMA caused a significant increase in systemic vascular resistance, concomitant with a significant fall in cardiac output. Sepsis caused an increase in myocardial blood flow and a redistribution of blood flow away from the pancreas and the stomach. Renal blood flow was not significantly elevated. During treatment with either compound, renal blood flow remained unchanged, despite a fall in cardiac output in the l-NMMA group. Unchanged renal blood flow combined with the restoration of arterial blood pressure caused a significant increase in urine output. Both l-NMMA and norepinephrine caused a redistribution of blood flow to the colon. Pancreatic blood flow was further reduced by l-NMMA but the oxygen extraction improved simultaneously, so that oxygen availability in the pancreas might have been unchanged. Because ischemic pancreatitis in sepsis is likely to trigger multiorgan failure, further investigations in that area are desirable.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Hepatic ischemia followed by reperfusion causes the release of a cascade of mediators, including tumor necrosis factor-a and epithelial neutrophil activating protein (ENA-78), which are important in the subsequent development of the lung and liver injury associated with this insult. We hypothesize that preferential post-ischemic shunting of blood into the nonischemic hepatic lobes at the time of reperfusion may increase the ischemic injury. To test this hypothesis, we utilized a rat model of lobar no-flow hepatic ischemia/reperfusion and removed the nonischemic hepatic lobes at the time of reperfusion to eliminate the preferential shunting of blood into the nonischemic tissues. We assessed pulmonary and hepatic tissue levels of ENA-78, pulmonary neutrophil influx and changes in pulmonary capillary permeability, and liver injury as measured by hepatic neutrophil influx and serum transaminase levels. Our results demonstrated that there were no significant differences in pulmonary and hepatic levels of ENA-78, or in the development of the lung and liver injury in animals undergoing resection of the nonischemic hepatic lobes at the time of reperfusion, as compared with animals undergoing hepatic ischemia/reperfusion alone.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID