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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Introduction: Perioperative alterations in perfusion lead to ischemia and reperfusion injury, and supplemental oxygen is administered during surgery to limit hypoxic injury but can lead to hyperoxia. We hypothesized that hyperoxia impairs endothelium-dependent and endothelium-independent vasodilation but not the vasodilatory response to heme-independent soluble guanylyl cyclase activation. Methods: We measured the effect of oxygen on vascular reactivity in mouse aortas. ⋯ Aorta 2-hydroxyethidium was 1419 pmol/mg of protein (25th-75th percentile = 1178-1513) in normoxia, 1993 (1831-2473) in moderate hyperoxia, and 2078 (1936-2922) in severe hyperoxia ( P = 0.008, effect across groups). Conclusions: Hyperoxia, compared with normoxia, impaired endothelium-dependent and endothelium-independent vasodilation but not the response to heme-independent soluble guanylyl cyclase activation, and hyperoxia increased vascular superoxide production. Results from this study could have important implications for patients receiving high concentrations of oxygen and at risk for ischemia reperfusion-mediated organ injury.
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Introduction: Sepsis impaired vascular integrity results in multiple organ failure. Circulating lactate level is positively correlated with sepsis-induced mortality. We investigated whether lactate plays a role in causing endothelial barrier dysfunction in sepsis. ⋯ Inhibition of GPR81 with its antagonist 3OBA attenuated vascular permeability and reversed HSPA12B expression in septic mice. Conclusions: The present study demonstrated a novel role of lactate in promoting vascular permeability by decreasing VE-cadherin junctions and tight junctions in endothelial cells. The deleterious effects of lactate in vascular hyperpermeability are mediated via HSPA12B- and GPR81-dependent signaling.
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We hypothesized that circulatory and jejunal mucosal blood flow would improve after 2-methyl-2thiazoline (2MT) administration in endotoxic shock. This study aimed to evaluate changes in systemic circulation and in superior mesenteric venous (SMV) blood flow and jejunal mucosal tissue blood flow of the intestinal vascular system over time after administration of 2MT in rabbits with endotoxic shock. We created four groups (n = 6 each): control group, LPS (1 mg/kg) group, 2MT (80 mg/kg) group, and LPS-2MT group. ⋯ An interaction between 2MT and LPS was observed for jejunal mucosal tissue blood flow from 90 to 180 min and at 240 min (P < 0.05). We showed that 2MT maintained MAP and improved SMV blood flow and jejunal mucosal tissue blood flow. In a rabbit model of endotoxic shock, 2MT had a positive effect on MAP and jejunal mucosal tissue blood flow.
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Background: Traumatic brain injury (TBI) is an underrecognized public health threat. The constitutive activation of microglia after TBI has been linked to long-term neurocognitive deficits and the progression of neurodegenerative disease. Evolving evidence indicates a critical role for the gut-brain axis in this process. ⋯ Our data demonstrated significant preservation of cortical volume and white matter connectivity after an injury compared with mice treated with vehicle alone. This preservation of neuroanatomy after TBI was associated with a marked reduction in inflammatory gene expression within the microglia of FMT-treated mice. Microglia from FMT-treated mice enriched pathways in the heat-shock response, which is known to play a neuroprotective role in TBI and other neurodegenerative disease processes.
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Objectives: Nosocomial pneumonia is a common complication in critically ill patients. The goal of this study was to examine the efficacy of the Toll-like receptor 4 agonist 3-deacyl phosphorylated hexacyl disaccharide (3D PHAD), in a clinically relevant murine model of pneumonia, and assess the cellular mechanisms that mediate the protective response. Design: Mice received intrapulmonary 3D PHAD (20 μg) or vehicle for 2 consecutive days before challenge with intrapulmonary Klebsiella pneumoniae (2.3 × 10 3 colony-forming units). ⋯ Lung innate leukocytes from 3D PHAD-treated mice had increased phagocytic capacity. Treatment with 3D PHAD alone increased cytokines in the lungs but decreased cytokines in plasma during K. pneumoniae pneumonia as compared with control. Conclusions: Intrapulmonary treatment with 3D PHAD augments innate immunity in the lung and facilitates resistance to K. pneumoniae pneumonia.