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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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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Although it is generally accepted that early defense mechanisms are controlled by cells of the innate immune system, T cells were found to be crucial for host resistance against acute septic peritonitis. However, the mechanisms by which T cells mediate protection are not fully understood. Here, we demonstrate mice deficient for recombinase-activating gene (RAG) 1, which lack mature B and T cells, showed enhanced susceptibility and impaired bacterial clearance in a model of acute septic peritonitis. ⋯ Direct analysis of T cells isolated from septic mice demonstrated that T cells respond to an acute septic challenge by increased production of IFN-gamma and IL-10. Moreover, bacterial numbers in spleens of septic RAG-1-deficient mice were significantly increased as compared with controls, suggesting that T cells are engaged in the early antibacterial immune defense during sepsis, possibly via the production of IFN-gamma. In summary, these results imply that T cells contribute to protective immune responses against acute systemic infections via their ability to produce crucial immune mediators.
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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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Comparative Study
Differential expression of toll-like receptor genes: sepsis compared with sterile inflammation 1 day before sepsis diagnosis.
Toll-like receptors (TLRs) are critical components of innate immunity. This study was designed to evaluate differential expression of genes for TLR and associated signal transduction molecules in critically ill patients developing sepsis compared with those with sterile inflammation. Uninfected critically ill patients with systemic inflammatory response syndrome were prospectively followed daily for development of sepsis. ⋯ Differential gene expression was noted for TLR receptors (eight genes), TLR intracellular signal transduction cascade molecules (27 genes), and TLR-related effector molecules (one gene). The TLR and downstream signaling genes are differentially expressed in critically ill patients developing sepsis compared with those with sterile inflammation. These expression differences occur before phenotypic-based diagnosis of clinical sepsis.
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Systemic and microvascular hemodynamic responses to hemorrhagic shock volume resuscitation with hypertonic saline followed by infusion of polymerized bovine hemoglobin (PBH) at different concentrations were studied in the hamster window chamber model to determine the role of plasma oxygen-carrying capacity and vasoactivity during resuscitation. Moderate hemorrhagic shock was induced by arterial controlled bleeding of 50% of blood volume (BV), and a hypovolemic state was maintained for 1 h. Volume was restituted by infusion of hypertonic saline (7.5% NaCl), 3.5% of BV, followed by 10% of BV of PBH at 2 different concentrations. ⋯ Only treatment with PBH4 restored perfusion and functional capillary density when compared with PBH13 and PBH0. Blood gas parameters and acid-base balance recovered proportionally to microvascular perfusion. Tissue PO2 was significantly improved in the PBH4 group, showing that limited restoration of oxygen-carrying capacity is beneficial and compensates for the effects of vasoactivity, a characteristic of molecular hemoglobin solutions proposed as blood substitutes.