Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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High-mobility group box 1 (HMGB-1) has been reported as a "late" proinflammatory mediator in sepsis. In vitro data have shown that HMGB-1 can induce activation of intracellular signaling pathways via interaction with at least three pattern recognition receptors: Toll-like receptor (TLR) 2, TLR-4, and the receptor for advanced glycation end products (RAGE). The objective of this study was to investigate the role of these receptors in the in vivo response to HMGB-1. ⋯ Compared with Wt mice, both TLR-4 and RAGE mice displayed lower TNF-alpha and IL-6 concentrations and lower neutrophil numbers in their peritoneal lavage fluid. In contrast, TLR-2 mice showed increased levels of TNF-alpha and IL-6 in their peritoneal cavity relative to Wt mice. These data indicate that HMGB-1 induces release of cytokines, activation of coagulation, and neutrophil recruitment in vivo via a mechanism that at least in part depends on TLR-4 and RAGE.
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Hydrogen sulfide (H2S) is a novel gaseous mediator produced by cystathionine-beta-synthase and cystathionine-gamma-lyase in the cardiovascular system, including the heart. Using a rat model of regional myocardial ischemia/reperfusion, we investigated the effects of an H2S donor (sodium hydrogen sulfide [NaHS]) on the infarct size and apoptosis caused by ischemia (25 min) and reperfusion (2 h). Furthermore, we investigated the potential mechanism(s) of the cardioprotective effect(s) afforded by NaHS. ⋯ Furthermore, NaHS attenuated the increase in the I/R-induced (1) phosphorylation of p38 mitogen-activated protein kinase and Jun N-terminal kinase, (2) translocation from the cytosol to the nucleus of the p65 subunit of nuclear factor-kappaB, (3) intercellular adhesion molecule 1 expression, (4) polymorphonuclear leukocyte accumulation, (5) myeloperoxidase activity, (6) malondialdehyde levels, and (7) nitrotyrosine staining determined in the AAR obtained from rat hearts subjected to regional myocardial I/R. In conclusion, we demonstrate that the cardioprotective effect of NaHS is secondary to a combination of antiapoptotic and anti-inflammatory effects. The antiapoptotic effect of NaHS may be in part due to the opening of the putative mitochondrial adenosine triphosphate-sensitive potassium channels.
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Ventilator-induced lung injury is mediated, at least in part, by TNF-alpha. We determined the effect of a recombinant human soluble TNF receptor fusion protein (etanercept) on mechanical ventilation (MV)-induced changes in a murine ventilator-induced lung injury model. After pretreatment with etanercept or placebo, C57Bl/6 mice were anesthetized and randomized to MV with either low tidal volumes (VT, approximately 7.5 mL/kg) or high VT ( approximately 15 mL/kg) for 5 h. ⋯ Lung wet-to-dry ratios, histopathology scores, and local protein levels in BALF, however, were not influenced by etanercept treatment. The number of caspase 3-positive cells was significantly higher in etanercept-treated animals. Inhibition of TNF by etanercept attenuates, in part, MV-induced changes.
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Severe sepsis and septic shock, often complicated by acute kidney injury (AKI), are the most common causes of mortality in noncoronary intensive care units (ICUs). This study investigates the outcomes of critically ill patients with sepsis and elucidates the association between prognosis and risk of renal failure, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage renal failure (RIFLE) classification. A total of 121 sepsis patients were admitted to ICU from June 2003 to January 2004. ⋯ Cumulative survival rates at 6-month follow-up after hospital discharge significantly (P < 0.05) differed between non-AKI versus RIFLE injury, non-AKI versus RIFLE failure (RIFLE-F), and RIFLE risk versus RIFLE F. At 6-month follow-up, full recovery of renal function was noted in 85% of surviving patients with AKI (RIFLE risk, RIFLE injury, and RIFLE-F). In conclusion, these findings are consistent with a role for RIFLE classification in accurately predicting in-hospital mortality and short-term prognosis in ICU sepsis patients.
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This study compares the effectiveness of the Pitt bacteremia score, the Charlson weighted index of comorbidity, and the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring systems for the prediction of mortality in intensive care unit (ICU) patients with sepsis using the retrospective observational method on 134 patients with ICU-acquired sepsis. The statistical analyses show several important findings. ⋯ Third, the Pitt bacteremia score and the APACHE II scores are positively related to mortality in patients with ICU-acquired sepsis. As the result of the analyses, the mortality rate in patients with sepsis in the ICU is better predicted with the Pitt bacteremia score because it provides better estimation of sensitivity and specificity than the APACHE II scoring system and the Charlson weighted index of comorbidity.