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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Lipopolysaccharide (LPS) or endotoxin can induce Toll-like receptor 4 signaling and cause microcirculatory dysfunction, which can lead to multiple organ dysfunction. The goal of this study was to investigate whether Toll-like receptor 4 antagonist, eritoran tetrasodium, can attenuate microcirculatory dysfunction in endotoxemic rats. Seventy-two male Wistar rats were divided into three groups as follows: control, LPS, and eritoran + LPS. ⋯ Eritoran also attenuated endotoxin-induced elevation in the serum level of D-dimer. In conclusion, we have established a promising rat protocol to investigate the intestinal microcirculation in endotoxemia. Our data indicate that eritoran can reduce microcirculatory dysfunction in endotoxemic rats.
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Despite significant advances in the care of critically ill patients, acute lung injury continues to be a complex problem with high mortality. The present study was designed to characterize early lipopolysaccharide (LPS)-induced pulmonary injury and small interfering RNA targeting focal adhesion kinase (FAK) as a possible therapeutic tool in the septic lung remodeling process. Male Wistar rats were assigned into endotoxemic group and control group. ⋯ There was fibrotic response in the lung characterized by increased amount in total and specific-type collagen. These data may explain the frequent clinical presentation during sepsis of reduced lung compliance, oxygen diffusion, and pulmonary hypertension. The fact that FAK silencing was protective against lung collagen deposition underscores the therapeutic potential of FAK targeting by small interfering RNA.
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Acute lung injury (ALI) is still a leading cause of morbidity and mortality in critically ill patients. Recently, our and other studies have found that hydrogen gas (H₂) treatment can ameliorate the lung injury induced by sepsis, ventilator, hyperoxia, and ischemia-reperfusion. However, the molecular mechanisms by which H₂ ameliorates lung injury remain unclear. ⋯ In addition, i.p. injection of 10 mL/kg hydrogen-rich saline also significantly attenuated the LPS-induced ALI. Collectively, these results demonstrate that molecular hydrogen treatment ameliorates LPS-induced ALI through reducing lung inflammation and apoptosis, which may be associated with the decreased NF-κB activity. Hydrogen gas may be useful as a novel therapy to treat ALI. munosorbent assay; H₂-hydrogen gas; HMGB1-high-mobility group box 1; HS-hydrogen-rich saline; i.t.-intratracheal; KC-keratinocyte-derived chemokine; LPS-lipopolysaccharide; MCP-1-monocyte chemoattractant protein 1; MIP-1α-macrophage inflammatory protein 1α; MIP-2-macrophage inflammatory protein 2; MPO-myeloperoxidase; PBS-phosphate-buffered saline; PMNs-polymorphonuclear neutrophils; TUNEL-deoxynucleotidyl transferase dUTP nick end labeling; W/D-wet-to-dry.
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Nitric oxide produced by inducible nitric oxide synthase (iNOS) contributes importantly to acute lung injury (ALI), but the specific contribution of neutrophil iNOS has not been defined. Thus, we defined the role of neutrophils and specifically neutrophil iNOS in a murine model of septic ALI. Four hours after cecal ligation/perforation, ALI was characterized by increases in pulmonary neutrophil infiltration (tissue myeloperoxidase activity, bronchoalveolar lavage neutrophils), microvascular leak of Evans blue (EB) dye-labeled albumin, and oxidant stress (8-isoprostane levels). ⋯ There were no significant differences between iNOS(+/+) and iNOS(-/-) neutrophils in phagocytosis, respiratory burst, or CD11a/b/CD18 surface expression, although septic shedding of CD62L was blunted in iNOS(-/-) neutrophils. Neutrophil iNOS contributes importantly to murine septic ALI in vivo, but not simply through a change in neutrophil phenotype. We speculate that neutrophil iNOS may modulate neutrophil-endothelial interactions in complex fashion, including regulation of transendothelial neutrophil migration and pulmonary neutrophil infiltration.
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The overactivation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) is considered a final common effector in ischemia/reperfusion (I/R) injury. The aim of the current study was to examine the precise time course of the activation of PARP in peripheral leukocytes and the reperfused myocardium tissue on myocardial I/R injury from the same rat and to identify the relationship between myocardial infarct size and the degree of PARP activation in circulating leukocytes. Another aim of the study was to test the effect of 3-aminobenzamide (a well-known and widely used PARP inhibitor) on the activation of PARP in the reperfused myocardium and peripheral leukocytes. ⋯ Immunohistochemical studies localized the staining of PAR primarily to the cardiac myocytes and vascular endothelial cells. At 6 h, there was a significant linear correlation between infarct size and PARP activity, whereas at 2 and 24 h, no relationship was found. The PARP inhibitor 3-aminobenzamide (3-AB, 20 mg kg⁻¹ i.v. injection 15 min before reperfusion, and every 2 h thereafter for 6 h) markedly reduced infarct size through depressing the activation of the enzyme in myocytes and peripheral leukocytes even when the treatment is initiated at 2 h after reperfusion.