摘要:

Severe sepsis is common, frequently fatal, and expensive. Many factors related to the pathogenesis of severe sepsis have made it difficult to effectively design clinical trials for the management of this disease. Hence, multiple trials of compounds for the treatment of severe sepsis have yielded largely negative results, except in small subsets of patients. This review provides a synopsis of the complex nature of sepsis and the problems associated with sepsis trials. Emphasis is placed on the difficulties in evaluating investigational agents in patients with severe sepsis because of the heterogeneity of the disorder, lack of correlation between animal and human models, the complexity of the insult and the host reaction, and the interaction between inflammation and coagulation in severe sepsis. Additionally, positive results from trials of steroids, intensive insulin therapy, and activated protein C (drotrecogin alfa [activated]) will be discussed. Because drotrecogin alfa (activated) is the only Food and Drug Administration-approved therapy for severe sepsis, the Phase 3 Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial results will be discussed in detail to help define a model for further clinical trials on severe sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

In our recent clinical study of damage control laparotomy, the abdominal compartment syndrome (ACS) emerged as an independent risk factor for postinjury multiple organ failure (MOF). We and others have shown previously that the ACS promotes the systemic production of proinflammatory cytokines. Our study objective was to develop a clinically relevant two-event animal model of postinjury MOF using the ACS as a second insult during systemic neutrophil priming to provoke organ dysfunction. Male adult rats underwent hemorrhagic shock (30 mmHg × 45 min) and were resuscitated with crystalloids and shed blood. The timing of postshock systemic neutrophil (PMN) priming was determined by the surface expression of CD11b via flow cytometry. Finding maximal PMN priming at 8 h, but no priming at 2 h (early) and 18 h (late), the ACS (25 mmHg × 60 min) was introduced at these time points. At 24 h postshock, lung injury was assessed by lung elastase concentration and Evans blue dye extravasation in bronchoalveolar lavage. Liver and renal injuries were determined by serum alanine aminotransferase, serum creatinine, and blood urea nitrogen. The ACS during the time of maximal systemic PMN priming (8 h) provoked lung and liver injury, but did not if introduced at 2 or 18 h postshock when there was no evidence of systemic PMN priming. The 24-h mortality of this two-event model was 33%. These findings corroborate the potential for the ACS to promote multiple organ injury when occurring at the time of systemic PMN priming. This clinically relevant two-event animal model of PMN organ injury may be useful in elucidating therapy strategies to prevent postinjury MOF.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Klebsiella pneumoniaeis a leading cause of gram-negative bacterial pneumonia, often resulting in bacteremia concurrent with the localized pulmonary infection. The beneficial role of tumor necrosis factor (TNF)-&agr; during pulmonary infection has been well documented; however, consequences of TNF-&agr; production during systemic bacterial infection are controversial. A murine model ofK. pneumoniaewas developed to address this important issue. Liver-associated TNF-&agr; mRNA was induced within 30 min after intravenous bacterial inoculation and remained elevated through 6 h before returning to near-baseline at 24 h postinfection. IntravenousK. pneumoniaeinfection induced liver cellular injury that was completely ablated when mice were pretreated with a neutralizing anti-TNF-&agr; antibody. Interestingly, this reduction in liver injury failed to translate into improved survival. Mice receiving anti-TNF-&agr; continued to succumb to the infection even out to day 10 postinfection. Bacterial clearance after TNF-&agr; neutralization was significantly impaired at later time points during infection. Correlating with impaired bacterial clearance was diminished production of liver-associated MIP-2, MIP-1&agr;, MCP-1, and interferon-&ggr;. Further evidence of diminished antibacterial immune responses was noted when the activational status of splenic natural killer cells in anti-TNF-&agr;-treated mice was examined 24 h postinfection. Natural killer cells displayed decreased CD69 expression. Combined, these data indicate that the beneficial effects of TNF-&agr; during systemicK. pneumoniaeinfection outweigh the detrimental effects of TNF-&agr;-mediated hepatocyte cellular injury. Anti-TNF-&agr; therapy, although preventing liver injury during blood-borne bacterial infection, results in a dampened anti-bacterial host response, resulting in decreased bacterial clearance and overall survival.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Hemorrhagic shock (HS) is a complex process that initiates a global stress response. However, the earliest signaling pathways responsible for initiating this response remain unidentified. We have investigated the involvement of the extracellular signal-regulated kinases (ERK 1/2; also known as p42/44) and their activation in the liver by angiotensin II in the early signal transduction after HS. Hemorrhage of mice to 25 mmHg for 30 min was associated with the activation of ERK 1/2 in the liver, and this was accompanied by a 6.7-fold elevation of circulating angiotensin II levels. Similar results were obtained in rats. Both the angiotensin II levels and ERK 1/2 phosphorylation were suppressed by administration of an angiotensin-converting enzyme inhibitor peptide. Plasma from shocked rats, but not shocked rats treated with the angiotensin-converting enzyme inhibitor, increased ERK 1/2 phosphorylation in cultured hepatocytes. Together, these data suggest that angiotensin II is an important stimulus for ERK 1/2 activation in the liver during HS.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The expression of heat shock or stress proteins (hsps) is a widespread response to stress that results in the protection of cells from subsequent insults, coined stress tolerance. Stress tolerance is apparently due to the preservation of several cellular structures and processes, such as translation. Protection of protein synthesis has been correlated with the presence of Hsp70. In the present study, Hsp70 was found to interact with translating ribosomes. This interaction is due to the preferential binding of Hsp70 to the 40S ribosomal subunit. Additionally, Hsp70 seems to interact weakly with nascent polypeptides within the 60S subunit. The interaction between Hsp70 and ribosomal subunits could also be observedin vitroconditions. Binding of Hsp70 to ribosomes was salt resistant, suggesting that this protein is not bound to transiently associated translational factors. Moreover, protection of protein synthesis requires new gene expression. We speculate that the binding of Hsp70 to ribosomes is part of a mechanism to guarantee the rapid and abundant protein synthesis during stress, particularly the translation of mRNAs encoding for hsps.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Hypertension is proposed as a risk factor among others (high age, diabetes mellitus, and pre- and intraoperative bleeding) for adverse outcomes, such as severe infections, leading to sepsis and to multiple organ failure as the most deleterious complication. Hypertension was modeled with spontaneous hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats and the infective complication by polymicrobial, peritoneal contamination, and infection (PCI). The concept of clinic modeling randomized trials was used to simulate clinical complexity, including a relevant antibiotic prophylaxis in combination with granulocyte-colony stimulating factor (G-CSF) and clinical trial conditions. Outcome parameters were: survival, systemic cytokines (protein), and organ-specific cytokine levels (mRNA). With low complexity (no prophylaxis), 28% of the animals in the Wistar and 50% in the SHR group survived (P= 0.17). Tumor necrosis factor-&agr; levels were lower in the liver of SHR vs. Wistar rats with PCI (P< 0.01). The anti-inflammatory cytokine interleukin (IL)-10 was expressed on a higher level in SHR with PCI compared with Wistar rats (P< 0.01). With increased complexity (antibiotic and G-CSF prophylaxis) the survival rate was increased from 50% in Wistar rats to 89% in SHR (P< 0.01) and the mRNA expression of IL-6 was decreased in the kidney of SHR (P< 0.05). Survival rate was 44% in the DS rats vs. 67% of the Wistar rats (P= 0.18). The mRNA expression of tumor necrosis factor-&agr; and IL-10 was reduced (P< 0.01) by pretreatment in the liver of DS rats with PCI. The hypertensive, genetically distinct SHR and DS rats express different patterns of pro- and anti-inflammatory cytokine levels after PCI. G-CSF and antibiotic prophylaxis increases only in SHR survival and decreases IL-6 mRNA expression in the kidney significantly.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Activation of the histaminergic system is characteristic of response to the action of adverse or potentially dangerous stimuli that disturb circulatory homeostasis, such as dehydration and changes in blood pressure. Previous study demonstrates that inhibition of histamineN-methyltransferase, which catabolizes histamine released from neurons, leads to the increase in endogenous central histamine concentrations and to the reversal of critical hemorrhagic hypotension. In the present study, the influence of intraperitoneal loading with histamine precursor l-histidine on central cardiovascular regulation was studied in a model of irreversible pressure-controlled hemorrhagic shock. Experiments were carried out in male Wistar rats anesthetized with ketamine/xylazine subjected to critical hemorrhagic hypotension of 20 to 25 mmHg, which resulted in the death of all control saline-treated animals within 30 min. l-Histidine administered in 5 min of critical hypotension produced dose-dependent increases in mean arterial pressure and heart rate (100–500 mg/kg), and a 100% survival rate of 2 h (500 mg/kg), whereas in normotensive animals, it did not influence cardiovascular parameters. The resuscitating effect of l-histidine (500 mg/kg) was associated with increases in histamine concentrations in the cerebral cortex (0.97 ± 0.11 nmol/g of wet tissue vs. 0.67 ± 0.22 nmol/g of wet tissue;P< 0.05), hypothalamus (4.78 ± 0.58 nmol/g of wet tissue vs. 4.08 ± 0.43 nmol/g of wet tissue;P< 0.01), and medulla oblongata (0.55 ± 0.18 nmol/g of wet tissue vs. 0.34 ± 0.09 nmol/g of wet tissue;P< 0.05), as well as with no changes in plasma histamine concentrations in comparison with the saline-treated group 20 min after injection. Pretreatment with (S)-&agr;-fluoromethylhistidine (&agr;-FMH, 0.5 mg intracerebroventricularly), an irreversible inhibitor of l-histidine decarboxylase, produced a decrease in central histamine concentrations and diminished volumes of blood required to achieve critical hypotension. Moreover, &agr;-FMH inhibited l-histidine-induced increases in central histamine concentrations and its resuscitating effect. In conclusion, the increase in central histamine concentrations after loading with l-histidine in rats subjected to critical hemorrhagic hypovolemia leads to the reversal of hypotension and the improvement in the survival rate of 2 h. On the other hand, inhibition of l-histidine decarboxylase activity, and thus histamine synthesis, produces a decrease in hemodynamic stability in hypotension, which suggests the histaminergic system-induced activation of compensatory mechanisms in hemorrhagic shock.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The pathogenesis of sepsis is still undetermined to a large extent. It is an established fact that female gender is associated with a lower mortality and that sex steroid hormones influence the immunologic response. Dehydroepiandrosterone (DHEA) seems to have a protective immunologic effect in sepsis. It is still unknown in which way DHEA influences the pathogenesis of sepsis. Therefore, the effect of DHEA application on cytokine concentrations in tumor necrosis factor (TNF) receptor (TNF-RI−/−) and interleukin-6 (IL-6−/−) knockout mice was determined. In a model of polymicrobial sepsis induced by coecal ligation and puncture (CLP), the effect of DHEA on survival and cytokine concentrations was examined. For clarification of the role of TNF-RI, CLP was performed in TNF-RI knockout mice (TNF-RI−/−). In addition, IL-6 knockout mice (IL-6−/−) were used to clarify the role of IL-6. Furthermore, experiments were performed in mice that were not genetically modified (wild type, WT). The protective effect of DHEA could be confirmed in this CLP model. DHEA application was associated with a reduction in mortality in WT animals. Moreover, DHEA-treated animals demonstrated a reduction in systemic inflammatory effects, as determined by proinflammatory cytokines TNF-&agr;, IL-1&bgr;, IL-6, and the antiinflammatory cytokine IL-10. In this work, it was shown that the TNF-RI is essential for survival after CLP. DHEA application was associated with a reduction of mortality of 100% in TNF-RI−/−mice after CLP to 50%. This result engages, that the effect of DHEA is TNF-RI independent. However, the application of DHEA had no influence on the mortality in IL-6−/−mice. It can be concluded that the protective effect of DHEA in polymicrobial sepsis is mediated IL-6 dependently. DHEA reduces the systemic inflammation, measurable via the proinflammatory cytokines TNF-&agr;, IL-1&bgr;, IL-6, and the antiinflammatory cytokine IL-10. IL-6 might be involved in the DHEA-mediated reduction of postseptic complications. In contrast, DHEA seems to be TNF-RI independent. Consequently, DHEA might be useful as an adjunct therapy for the immune modulation in sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Activation of the complement (C) cascade is known to play a key role in the adverse immune consequences of hemorrhagic trauma with subsequent shock and resuscitation. However, it is not clear whether hypovolemia per se, without trauma and resuscitation, can also lead to C activation. To address this question, we studied the presence, kinetics, and cause of C activation in a porcine model of hemorrhagic shock and resuscitation in the absence of trauma. Pigs were bled to and kept at 35 mmHg for 90 min, followed by hypotensive resuscitation with different fluids and, finally, with shed blood. The animals developed severe lactic acidosis between 30 and 90 min, which was accompanied by a trend for initial rise and subsequent 40% drop of CH50/mL, indicating massive C activation even before resuscitation, i.e., before reperfusion damage could have occurred. Resuscitation with plasma expanders caused 20% additional C consumption, whereas whole blood raised CH50/mL. Plasma C5a decreased initially and then significantly increased at 60 and 180 min, whereas thromboxane B2showed a 3-fold increase at 30 and 60 min. Plasma LPS was also increased above baseline at 90 and 180 min. Inin vitrostudies with pig blood, spontaneous C5a formation, as well as zymosan-induced C consumption, was significantly enhanced under the conditions of lactic acidosis. Our data suggest that lactic acidosis, endotoxemia, and possibly other ischemia-related tissue alterations act in a vicious cycle in inducing C activation and, hence, aggravation of shock. The biphasic course of CH50/mL and C5a changes may reflect yet unrecognized physiological responses to hemorrhage-related C activation.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Pancreatic tissue homogenate induces a powerful pathophysiologic response sufficient to produce lethal shock in a rat. However, limited progress has been made in the biochemical characterization of these pancreas-derived active factors or their mechanisms of action. It has been shown that the pancreas is a major source of these shock-inducing factors and that they are generated by pancreatic proteinases. Porcine pancreas was homogenized and the filtered homogenate was subjected to organic extraction both before and after incubation for 2.5 h at 37°C. The aqueous and lipid extracts of pancreatic homogenates were collected and analyzed for their ability to activate human neutrophils and to induce lethal shock in the rat. Neutrophil activation, a presumed hallmark of shock, was determined by chemiluminescence and myeloperoxidase (MPO) release. Only the intact homogenate and lipid extracts stimulated the neutrophils, and the aqueous extracts proved to be inactive. Neutrophils exhibited enhanced cellular activation when exposed to substimulatory levels of either formyl-methionyl-leucyl-phenylalanine (FMLP) or platelet-activating factor (PAF) followed by substimulatory levels of the lipid extracts, but not by the aqueous extracts. Both the lipid and aqueous extracts induced dramatic decreases in heart rate and blood pressure when injected in the rat, often resulting in lethal shock. In all cases, incubation of the homogenates at 37°C enhanced the potency of the extracts. Our results demonstrated that the pancreas-derived homogenate and lipid factors were capable of inducing both neutrophil activation and shock. These results support the hypothesis that shock is produced via neutrophils that have been activated by inflammatory components. However, the shock-inducing factors in the aqueous extracts (i.e., hydrophilic fraction of the homogenate) apparently function via a pathway independent of neutrophil activation. This is the first evidence that there are both hydrophobic and hydrophilic factors generated in tissue homogenates capable of inducing shock, and that these different chemical classes of factors appear to function via separate mechanisms.

ISSN:1073-2322    

出版商:OVID    

年代:2003

数据来源: OVID