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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Convalescence in humans after severe sepsis occurs over weeks to months and is associated with prolonged functional disabilities and impaired quality-adjusted survival. While much is known regarding the acute early phase of sepsis, there is a knowledge gap pertaining to restoration of muscle mass and function after elimination of the septic nidus. We used a sepsis-recovery model-where cecal-ligation-puncture (CLP) was performed in adult male mice followed 24 h later by removal of the cecum and antibiotic treatment-to assess changes in the abundance of muscle contractile proteins and function during the acute phase of sepsis (24 h post-CLP) and during the recovery phase (day 10 post-CLP). ⋯ Contractile defects during sepsis-recovery were associated with 50% to 90% reductions in thin filament (troponin T, troponin I, tropomyosin, α-sarcomeric actin), thick filament (myosin heavy and myosin light chains), Z-disc (α-actinin 3), and M-band (myomesin-2) proteins, but no change in the intermediate filaments desmin and vimentin. During sepsis recovery, myofibrillar protein synthesis did not differ from control, but synthesis of sarcoplasmic proteins was increased 60%. These data suggest intrinsic defects in muscle contractile function exist during the recovery phase of sepsis and may negatively impact convalescence.
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Knowledge about the neuroinflammatory state during months after sudden cardiac arrest is scarce. Neuroinflammation is mediated by cells that express the 18 kDa translocator protein (TSPO). We determined the time course of TSPO-expressing cells in a rat model of sudden cardiac arrest using longitudinal in vivo positron emission tomography (PET) imaging with the TSPO-specific tracer [18F]DAA1106 over a period of 6 months. ⋯ After sudden cardiac arrest, TSPO remains expressed over the long-term. Sustainable treatment options for neuroinflammation may be considered to improve cognitive functions after sudden cardiac arrest.
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Although hypothermia is independently associated with an increased mortality in trauma patients, it might be an effective therapeutic approach for otherwise lethal hemorrhage. The effect of hypothermia on microcirculation, however, has been poorly studied in this setting. Our goal was to characterize the effects of hypothermia on microcirculation in normal conditions and in severe hemorrhagic shock. ⋯ This is the first experimental study assessing the effect of systemic hypothermia on microcirculation in severe hemorrhagic shock. The main finding was that hypothermia did not hamper additionally the microcirculatory derangements induced by hemorrhagic shock. In addition, renal microcirculation was more susceptible to hemorrhagic shock than villi and sublingual microcirculation.
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We recently demonstrated that fibrinogen stabilizes syndecan-1 on the endothelial cell (EC) surface and contributes to EC barrier protection, though the intracellular signaling pathway remains unclear. P21 (Rac1) activated kinase 1 (PAK1) is a protein kinase involved in intracellular signaling leading to actin cytoskeleton rearrangement and plays an important role in maintaining endothelial barrier integrity. We therefore hypothesized that fibrinogen binding to syndecan-1 activated the PAK1 pathway. ⋯ We have identified a novel pathway by which fibrinogen activates PAK1 signaling to stimulate/dephosphorylate cofilin, leading to disassembly of stress fibers and reduction of endothelial permeability.
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Sepsis is a life-threatening syndrome which can progress to multiple organ dysfunction with high mortality. Intestinal barrier failure exerts a central role in the pathophysiological sequence of events that lead from sepsis to multiple organ dysfunction. The present study investigated the role of hydrocortisone (HC) administration and fecal microbiota transplantation (FMT) in several parameters of the gut barrier integrity, immune activation, and survival, in a model of polymicrobial sepsis in rats. ⋯ Fecal microbiota transplantation and stress dose hydrocortisone administration in septic rats induce a multifactorial improvement of the gut mechanical and immunological barriers, preventing endotoxemia and leading to improved survival.