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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Thrombomodulin (TM) is expressed on the surface of monocytes and is a key regulator of actual immune capacity. Propofol is an anesthetic agent that exerts anti-inflammatory effects. The objective of this study was to determine whether propofol could modulate TM in TNF-α-stimulated monocytes. ⋯ In conclusion, the inhibition of TM expression in TNF-α-treated monocytes was mediated by the activation of NADPH oxidase and the expression of TTP. Propofol may inhibit the downregulation of TM by mediating NADPH oxidase and TTP inactivation and through the activation of HuR in vitro and in vivo. Utilizing TTP and HuR to control TM expression may be a promising approach for controlling systemic inflammation, and propofol may possess potential implications for the clinical immunity of monocytes after anesthesia or surgery.
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Hemorrhagic shock and splanchnic arterial occlusion (SAO) followed by reperfusion are associated with high mortality. However, rapid cardiovascular failure and death may also occur before reperfusion in hemorrhagic shock and SAO. We show in a rat SAO model that, upon gut ischemia, mean arterial blood pressure transiently elevates and then drops fatally in one of two time courses: (i) gradually over ∼1 to 3 h or (ii) rapidly (often by >80 mmHg) over a period of 1 to 6 min. ⋯ Total subdiaphragmatic vagotomy or glycopyrrolate treatment significantly reduced the incidence to 0% (P < 0.008), although slow fatal pressure drops still occurred. ANGD did not prevent FFPDs, but delayed onset of slow fatal pressure drops (P < 0.013). These results suggest that gut ischemia can cause sudden death via an autonomic nervous system mechanism and that SAO with Glucose and xylazine may serve as a useful model for the study of neurogenic shock or autonomic dysregulation associated with sudden death.
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Mesenchymal stem cells (MSCs) possess immunomodulatory properties and may curtail the inflammatory response that characterizes sepsis and other systemic inflammatory states. We aimed to determine whether intravenous infusion of MSCs is associated with reduced inflammation and improved myocardial function in a rat model of endotoxemia. Adult Sprague-Dawley rats were administered saline (vehicle) or LPS (5 mg/kg) via tail vein injection. ⋯ Treatment with MSCs, however, was associated with significant reductions in serum levels of IL-1β and IL-6 and in myocardial levels of TNF-α, IL-1β, and IL-6. In addition, treatment with MSCs was associated with a further increase in serum IL-10. Infusion of MSCs modulates the systemic inflammatory response and is associated with improved cardiac function during endotoxemia.
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Multiple organ dysfunction syndrome (MODS) is a systemic inflammatory event that can result in organ damage, failure, and high risk of mortality. The aim of this study was to evaluate the possible role of glucocorticoid-induced TNFR-related (GITR) on zymosan-induced MODS. Mice were allocated into one GITR knockout (GITR-KO) and two GITR wild-type (GITR-WT) experimental groups. ⋯ We here show that GITR plays a role in the modulation of experimental MODS. In particular, we show that genetic inhibition of GITR expression, in GITR-KO mice, or administration of soluble GITR-Fc receptor in GITR-WT mice, reduces inflammation, organ tissue damage, and mortality. Results, while confirming the proinflammatory role of GITR, extend our observations indicating that GITR plays a role in zymosan-induced inflammation and MODS.
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The liver is likely exposed to high levels of hydrogen sulfide (H2S) from endogenous hepatic synthesis and exogenous sources from the gastrointestinal tract. Little is known about the consequence of H2S exposure on the liver or hepatic regulation of H2S levels. We hypothesized that the liver has a high capacity to metabolize H2S and that H2S oxidation is decreased during sepsis, a condition in which hepatic O2 is limited and H2S synthesis is increased. ⋯ Infusion of H2S increased the NADH/NAD+ ratio (645 gray-scale-unit increase, P = 0.035) and decreased hepatic O2 availability visualized with Ru(Phen)3(2+) (439 gray-scale-unit increase, P = 0.040). We conclude that the liver has a high hepatic capacity for H2S metabolism. Moreover, H2S oxidation consumes available oxygen and may exacerbate the tissue hypoxia associated with sepsis.