摘要:

Two contrasting roles, one beneficial and the injurious, have been proposed for tumor necrosis factor (TNF) in the pathogenesis of cerebral ischemia. Reported here are results obtained in a standard model of permanent focal cortical ischemia in rats, in which the volume of cerebral infarction is measured after permanent occlusion of the middle cerebral artery. Administration of neutralizing anti-rat TNF antibodies (PI14) into the brain cortex significantly reduced ischemic brain damage (85% reduced infarct volume as compared with preimmune-treated controls). Similar results were achieved by systemic administration of CNI-1493, a recently described tetravalent guanylhydrazone compound, which effectively inhibited endogenous brain TNF synthesis and conferred significant protection against the development of cerebral infarction (80% reduced infarct volume as compared with vehicle controls treated 1 h postischemia with 10 mg/kg). PI14 anti-TNF and CNI-1493 were each cerebroprotective when given within a clinically relevant time window for up to 2 h after the onset of ischemia. These findings establish an important, pathophysiological role of TNF in mediating the progression of ischemic brain damage, and suggest that inhibiting TNF with CNI-1493 may be beneficial in the future treatment of stroke.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The endogenous metabolite adenosine has been recognized as a protective agent in the setting of ischemia-reperfusion. Because the formation of adenosine during ischemia is closely linked to ATP catabolism, and its actions antagonize the deleterious metabolic and cardiovascular consequences of ischemia, it has been named a “retaliatory” metabolite. During recent years, however, the insight into its diverse scope of anti-inflammatory actions has increased considerably. In this review, the beneficial metabolic and cardiovascular actions of adenosine in ischemia and reperfusion are briefly outlined, followed by an extensive discussion of the established and putative anti-inflammatory actions of adenosine in the inflammatory response to ischemia and reperfusion. It is demonstrated that adenosine interferes with activated neutrophil function, neutrophil-endothelial adhesive interactions, the production and release of various inflammatory mediators, the expression of adhesion molecules, and that it activates cellular antioxidant defense systems, thus providing protective effects at multiple levels in the pathogenesis of ischemia and reperfusion. Finally, several potential pharmacological strategies to enhance the “natural defense mechanism” provided by endogenous adenosine are presented.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Lazaroids are developed nonglucocorticoid analogues of methylprednisolone with multiple actions, including the scavenging of reactive oxygen species, the attenuation of inflammation, and the stabilization of biological membranes. In various experimental models, lazaroids were shown to enhance recovery from ischemia-reperfusion injury, central nervous system inflammation, oxidant stress, and panendothelial activation and injury; sepsis might be another important indication for the use of lazaroids. Administration of different lazaroids in experimental endotoxemia and other forms of sepsis indeed showed improvement of biological and hemodynamic parameters, attenuation of inflammation, preservation of oxygenation, and protection of endothelial cell integrity. Further research is needed to determine the effects of these drugs on organ function, mediator synthesis and release, and survival, before appropriate therapeutic protocols for their use in clinical sepsis can be developed.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Activation of thrombin and of the coagulation system plays an important role in the pathophysiology of sepsis-associated organ dysfunction. Antithrombin III (AT III) is a natural inhibitor of thrombin, a central procoagulatory factor with pleiotropic activities. Experimental supplementation of AT III improved coagulation parameters and ameliorated organ dysfunction. To determine whether long-term AT III supplementation has beneficial effects on organ function, we conducted a randomized, prospective study in surgical patients with severe sepsis. The study evaluated the long-term effect of AT III supplementation (duration of treatment: 14 days). After randomization (AT III vs. control group), AT III was infused continuously over 14 days to obtain plasma AT III activities > 120%. Forty consecutive patients were recruited (20 AT III/20 control group). Eleven patients had a rapid fatal course and did not met the criterion of a 14 day treatment period. From these 11 patients, 8 patients (5 AT III/3 control group) died within 72 h due to septic shock. The remaining 14 AT III patients and 15 controls survived 14 days and showed no differences in baseline parameters of organ function. AT III caused a disappearance of disseminated intravascular coagulation (DIC) in all patients with DIC, whereas in control patients, the frequency of DIC remained constant (p< .05). In AT III patients a progressive increase in oxygenation index (Pao2/Fio2ratio) and a continuous decrease in pulmonary hypertension index (mean pulmonary artery pressure/mean arterial pressure (PAP/MAP) ratio) indicated an improvement of lung function (p< .05 vs. control). AT III prevented the continuous rise in total serum bilirubin concentration observed in control patients and diminished the frequency of artificial renal support therapy (p< .05). Long-term supplementation with AT III may improve lung function and prevent the development of septic liver and kidney failure in patients with severe sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The difference in CO2tension between venous and arterial blood (ΔPco2) increases in low-flow states. Therefore, ΔPco2has been suggested as an additional variable in the monitoring of perfusion. We measured CO2tensions in arterial, mixed venous, hepatic venous, and femoral venous blood in 42 postoperative cardiac surgery patients. Splanchnic and leg blood flow was measured with dye dilution. Forty-three preoperative abdominal surgery patients served as controls. Systemic and femoral ΔPco2was increased in cardiac patients, whereas there was no difference in splanchnic ΔPco2between the groups. In cardiac patients, systemic ΔPco2correlated well with both splanchnic and femoral ΔPco2(r2= .74 andr2= .56, respectively). Femoral ΔPco2was higher than splanchnic ΔPco2(1.27 ± .44 kPa versus .66 ± .41;p< .001) after cardiac surgery, but not in the control group. The correlation between ΔPco2and respective blood flow was weak in the whole body, the splanchnic region, and the leg. When splanchnic blood flow was low, systemic and splanchnic ΔPco2varied widely. In the cardiac patients with an increased systemic ΔPco2(> .93 kPa), systemic and regional blood flow was low, but there were no differences in systemic or regional oxygen consumption or lactate levels. After cardiac surgery, high systemic ΔPco2is associated with marginal systemic and regional perfusion. The adequacy of regional blood flow cannot be assessed on the basis of the systemic ΔPco2.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The overzealous production of proinflammatory cytokines in sepsis can result in shock, multiorgan dysfunction, and even death. In this study we assessed the role of endogenously produced interleukin (IL)-12 in murine models of endotoxemia and Gram-negative peritoneal sepsis. Initial studies indicated that intraperitoneal lipopolysaccharide (LPS) administration to mice induced a significant time-dependent increase in plasma, lung, and liver IL-12 levels. Passive immunization with anti-IL-12 serum intraperitoneally before LPS resulted in a marked reduction in plasma levels of tumor necrosis factor and interferon-γ. Furthermore, we observed an increase in endotoxin-induced mortality in mice transiently overexpressing murine IL-12 using a recombinant adenoviral vector (Ad5 mIL-12) administered intraperitoneally. Neutralization of tumor necrosis factor or interferon-γ in animals overexpressing IL-12 resulted in significant reductions in LPS-induced mortality, suggesting that the mechanism whereby IL-12 increases LPS-induced mortality is primarily mediated by the enhancement of these cytokines. In contrast, we observed no survival benefit in animals passively immunized with anti-IL-12 serum before the intraperitoneal administration of 2 x 108liveEscherichia coli.Interestingly, there was an approximately 70-fold increase in peritoneal fluidE. colicolony-forming units and the early onset of bacteremia in animals treated with anti-IL-12 serum, as compared with control animals. These results indicate that IL-12 is produced in response to LPS exposure, and the neutralization of this cytokine improves survival in endotoxin-challenged animals. However, IL-12 represents an essential component of antibacterial host defense, as anti-IL-12 therapy results in significant impairment in the host's ability to clear Gram-negative bacterial infection.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

This study investigated the expression and regulation of intercellular adhesion molecule-1 (ICAM-1) on human polymorphonuclear neutrophils (PMNs), and its potential role in PMN-PMN adherence and aggregation as observed during systemic inflammatory response syndrome. Normal human PMNs were found to express ICAM-1 with 90% positive population, and this expression was augmented by endotoxin (lipopolysaccharide, LPS) and tumor necrosis factor-α (TNF-α) stimulation. The presence of ICAM-1 mRNA in human PMNs was further detected by reverse transcription-polymerase chain reaction before and after LPS and TNF-α treatment. Furthermore, incubation of PMNs with LPS and TNF-α resulted in significant increases in PMN-PMN adherence and aggregation, while addition of either anti ICAM-1 mAb or anti CD11b/CD18 mAb significantly inhibited LPS and TNF-α-mediated PMN-PMN adherence and aggregation. These novel findings demonstrate that ICAM-1 is expressed on human PMNs and responsible for PMN aggregation, and suggest that the interaction between ICAM-1 and CD11b/CD18 may be the molecular basis for PMN aggregation and clumping in the microcirculation during systemic inflammatory response syndrome.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

There is evidence that proinflammatory cytokines are involved in the regulation of muscle protein breakdown in various catabolic conditions but the mechanisms are not fully understood. Previous studies suggest that cytokines reduce circulating and tissue levels of insulin-like growth factor-I (IGF-I) and may block the anabolic effects of the hormone in certain cell types and tissues. We tested the hypothesis that a mixture of tumor necrosis factor α, interleukin-1α, and interferon-γ block the anabolic effects of IGF-I in skeletal muscle. Muscles from burned or unburned rats were incubated in the absence or presence of 1 μg/mL of IGF-I with or without the addition of the cytokines. As expected, IGF-I stimulated protein synthesis and inhibited protein breakdown in incubated muscles. The cytokines did not influence protein turnover rates in muscles incubated with or without IGF-I. In additional experiments, the effects of IGF-I on glucose uptake and lactate production were tested. IGF-I increased glucose uptake ∼2.5-fold and stimulated lactate production ∼5-fold. These effects of the hormone were significantly inhibited by the cytokine mixture. The results suggest that cytokines do not induce protein catabolism by directly inhibiting the anabolic effects of IGF-I in muscle tissue. The inhibitory effects of the cytokines on IGF-I-stimulated glucose transport and lactate production suggest that the lack of effect of cytokines on protein metabolism was not due to a metabolic unresponsiveness of the incubated muscles to the cytokines.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Endotoxin has profound effects on nitric oxide (NO) production, and considerable controversies exist as to whether these alterations are beneficial or deleterious. Increased mortality has been reported from nonselective inhibition of NO synthase. Results from selective inhibition of the inducible isoform (iNOS) appear largely positive. In a model of rat endotoxemia we have compared the early effects on hepatic morphology and function of selective and nonselective NO inhibition. Two hours after endotoxin injection (5 mg/kg intraportally) the rats were treated with either the selective iNOS inhibitor aminoethyl isothiourea (AE-ITU, 10 mg/kg), the nonselective NOS inhibitorNG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), or normal saline. The animals were observed for another hour. Using an immunohistochemical method, induction of iNOS was demonstrated in various tissues in all slices examined. No unequivocal benefit from NO inhibition was noted. Electron microscopic examination revealed widespread alterations of liver morphology, without obvious differences between the groups. Liver function, as assessed by ketone body ratio, hepatic venous acid base values, and bile production, was generally more adversely affected after NO inhibition. Even with the iNOS selective inhibitor AE-ITU no benefit was noted. We conclude that during the early phases of endotoxemia therapeutic reduction of NO production has no positive effects on liver function or morphology.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

This study was performed to quantify the impact of Haldane effect (HE) on the relationship between O2extraction (O2Ex; mL O2/dL blood) and venous pH in 247 measurements performed in 91 septic patients (73 patients with intra-abdominal sepsis, 11 with retroperitoneal abscesses, 6 with severe cholangitis, and 1 with gangrenous fasciitis). The severity of sepsis varied from relatively compensated to extremely diseased conditions. This allowed a detailed assessment of the impact of HE over a wide range of cardiorespiratory and metabolic abnormalities. A recently developed model was used to quantify blood CO2exchange and Haldane relationships and, in particular, the buffering of venous pH allowed by O2Ex (O2-linked H+binding) on the basis of arterial and mixed venous blood gas measurements. Arterio-venous pH difference (a-vDpH) was .033 ± .024 (mean ± SD). It increased with venoarterial CO2concentration difference (v-aDCO2; mL CO2/dL blood), but the increase was moderated by a simultaneous increase in O2Ex, as the likely consequence of HE: a-vDpH = .006 + .017 (v-aDCO2) - .009 (O2Ex) [r2= .96,p≪ .001]. To confirm this, the moderation of a-vDpH allowed by the HE (DpH) was calculated. A first component, due to O2-linked H+binding, had a value of .016 ± .012, and a second component, due to the Haldane-mediated reduction in venous CO2tension and plasma carbonic acid concentration, had a value of .019 ± .006. Their sum (total DpH) was .033 ± .017 and was related directly and strongly to O2Ex: DpH = -.002 + .009 (O2Ex) [r2= .85,p≪ .001], thus confirming the quantitative impact of HE in moderating the decrease in venous pH relative to arterial pH. The loss of this effect was responsible for the larger decreases in venous pH observed in hypodynamic patients developing impaired O2Ex. These results allow an easy quantification of the Haldane component, separated from the other components affecting pH, and are also useful for assessing the protective role exerted by HE against excessive decreases in venous pH in circulatory failure.

ISSN:1073-2322    

出版商:OVID    

年代:1997

数据来源: OVID