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 (HMGB1) is a late mediator of the systemic inflammation associated with sepsis. Recently, HMGB1 has been shown in animals to be a mediator of hemorrhage-induced organ dysfunction. However, the time course of plasma HMGB1 elevations after trauma in humans remains to be elucidated. ⋯ Plasma HMGB1 is significantly increased within 1 h of trauma in humans with marked elevations occurring from 2 to 6 h postinjury. These results suggest that, in contrast to sepsis, HMGB1 release is an early event after traumatic injury in humans. Thus, HMGB1 may be integral to the early inflammatory response to trauma and is a potential target for future therapeutics.
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Toll-like receptor 4 (TLR4) plays a major role in regulating the innate immune response, which is related to postoperative complications. Although inflammatory capacity and TNF-alpha synthesis were altered on monocytes after cardiopulmonary bypass (CPB), whether the CPB and the CPB-induced TNF-alpha affect TLR4 expression on monocytes have not yet clarified. We speculate that the changing of TNF-alpha level during CPB may be involved in monocytic TLR4 expression. ⋯ We also demonstrated in clinical samples with confocal microscopy and flow cytometry that CPB led to an elevation of TTP in monocytes. In conclusion, CPB and TNF-alpha decrease TLR4 expression on monocytes; TTP expression and mitogen-activated protein kinase-signaling pathways play critical roles in CPB- and TNF-alpha-mediated decreases of TLR4 on monocytes. Our results suggest that using TTP to control cytokine message decay rate may be a promising approach for controlling system inflammation and preventing post-CPB complications.
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Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, plays a key role in cardiac dysfunction in sepsis. Low circulating levels of insulin-like growth factor 1 (IGF-1) are found in sepsis, although the influence of IGF-1 on septic cardiac defect is unknown. This study was designed to examine the impact of IGF-1 on LPS-induced cardiac contractile and intracellular Ca2+ dysfunction, activation of stress signal and endoplasmic reticulum (ER) stress. ⋯ Interestingly, these LPS-induced changes in mechanical and intracellular Ca2+ properties, ROS, protein carbonyl, apoptosis, stress signal activation, and ER stress markers were effectively ablated by IGF-1. In vitro LPS exposure (1 microg mL(-1)) produced cardiomyocyte mechanical dysfunction reminiscent of the in vivo setting, which was alleviated by exogenous IGF-1 (50 nM). These data collectively suggested a beneficial of IGF-1 in the management of cardiac dysfunction under sepsis.
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Acute lung injury following intestinal I/R depends on neutrophil-endothelial cell interactions and on cytokines drained from the gut through the lymph. Among the mediators generated during I/R, increased serum levels of IL-6 and NO are also found and might be involved in acute lung injury. Once intestinal ischemia itself may be a factor of tissue injury, in this study, we investigated the presence of IL-6 in lymph after intestinal ischemia and its effects on human umbilical vein endothelial cells (HUVECs) detachment. ⋯ Intestinal ischemia and absence of constitutive NOS activity leading to additional intestinal stress both cause release of IL-6 and increase of lung microvascular permeability. Because anti-IL-6 prevented the endothelial cell injury caused by lymph at the ischemia period, the lymph-borne IL-6 might be involved with endothelial cell activation. At the reperfusion period, this cytokine does not seem to be modulated by NO.
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The aim of the present study was to evaluate the role of endogenous and exogenous peroxisome proliferator-activated receptor alpha (PPAR-alpha), a nuclear receptor, on the regulation of inflammation in macrophages. To address this question, we have stimulated peritoneal macrophages from PPAR-alpha wild-type mice and PPAR-alpha knockout mice (PPAR-alpha) with 10 microg/mL LPS and 100 U/mL IFN-gamma. We report here that the absence of a functional PPAR-alpha gene in PPAR-alpha knockout mice resulted in a significant augmentation of various inflammatory parameters in peritoneal macrophages. ⋯ To elucidate whether the protective effects of clofibrate is related to activation of the PPAR-alpha receptor, we also investigated the effect of clofibrate treatment on PPAR-alpha-deficient mice. The absence of the PPAR-alpha receptor significantly abolished the protective effect of the PPAR-alpha agonist against LPS/IFN-gamma-induced macrophage inflammation. In conclusion, our study demonstrates that the endogenous and exogenous PPAR-alpha ligands reduce the degree of macrophage inflammation caused by LPS/IFN-gamma stimulation.