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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Septic shock is a leading cause of mortality in intensive care units throughout the world. While this disease state represents a highly complex pathophysiology involving numerous organ systems, the early approach to care includes adequate hemodynamic support traditionally achieved via infusions of vasoactive medications after adequate fluid resuscitation. ⋯ Hydrocortisone and vasopressin are endocrine system hormone analogues that target the acute neuroendocrine imbalance associated with septic shock. This clinically focused annotated review describes the pathophysiological mechanisms behind their use and explores the potential clinical roles of early administration and synergy when combined.
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Clinical Trial
Iloprost, prostaglandin E1, and papaverine relax human mesenteric arteries with similar potency.
Nonocclusive mesenteric ischemia (NOMI) is accompanied by mesenteric artery spasms that are at least in part due to endothelin system activation. Acute treatment includes intra-arterial infusion of vasodilators such as iloprost, prostaglandin E1 (PGE1), and papaverine. Their effectiveness is not well characterized in human mesenteric arteries. We directly compared their potency to relax isolated human mesenteric arteries. To explore the potential of Rock inhibition to treat mesenteric artery spasms, we tested if endothelin-1 (ET-1)-induced mesenteric artery constrictions depend on rho kinase (Rock). ⋯ Iloprost, PGE1, and papaverine have a similar potency to relax mesenteric arteries. Our data suggest that iloprost but not Rock inhibition may be particularly useful to treat ET-1-induced spasms of distal mesenteric arteries.
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Neutrophils are a population of inflammatory cells involved in acute lung injury (ALI), and lipopolysaccharide (LPS)-induced prolonged neutrophil survival and delayed neutrophil apoptosis hinder the alleviation of lung inflammation. Myosin light-chain kinase (MLCK) involved the RhoA/Rho kinase signaling pathway responsible for the cytoskeletal arrangement, and previous studies have revealed that inhibition of MLCK induces apoptosis in vitro and in vivo. In this study, glycogen-induced neutrophils isolated from rats or mice were incubated with ML-7, a MLCK-specific inhibitor, and LPS-induced ALI mice administrated with ML-7 were investigated, to demonstrate the roles of MLCK in neutrophil apoptosis as well as its possibility of contributing to the clearance of inflammation. ⋯ ML-7 promoted elimination of inflammation possibly by accelerating neutrophil apoptosis and macrophage-mediated clearance. Moreover, ML-7 also reduced the LPS-induced production of proinflammatory cytokines interleukin-1β and tumor necrosis factor-α, and the activity of myeloperoxidase. Taken together, the present study uncovers a hitherto uncharacterized role of MLCK in neutrophil apoptosis that contributes to the alleviation of inflammation in response to LPS.
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Hyperglycemia is a common feature of septic patients and has been associated with poor outcome and high mortality. In contrast, insulin has been shown to decrease mortality and to prevent the incidence of multiorgan failure but is often associated with deleterious hypoglycemia. Protein Tyrosine Phosphatase 1B (PTP1B) is a negative regulator of both insulin signaling and NO production, and has been shown to be an aggravating factor in septic shock. ⋯ PTP1B gene deletion significantly limited CLP-induced insulin resistance, improved AMP-activated protein kinase signaling pathway and Glucose Transporter 4 translocation, and decreased inflammation. These effects were associated with a reduction of sepsis-induced endothelial dysfunction/impaired NO production and especially of insulin-mediated dilatation. This modulation of insulin resistance may contribute to the beneficial effect of PTP1B blockade in septic shock, especially in terms of inflammation and cardiac metabolism.
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This study investigated the effects of glycyrrhizin (GR) on the ratio of myeloid-derived suppressor cells (MDSCs) to cluster of differentiation (CD)11b+Gr1 myeloid cells in the heart and lungs in lipopolysaccharide (LPS)-induced septic mice. ⋯ GR exhibited protective effects on the heart and lungs in LPS-induced septic mice. The effects were associated with an elevated ratio of MDSCs to CD11b+Gr1 myeloid cells and the inhibition of cytokine release and TLR4 expression after GR injection.