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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Background: Protein kinase ataxia telangiectasia mutated (ATM) regulates the function of endothelial cells and responds quickly to endotoxin. However, the function of ATM in lipopolysaccharide (LPS)-induced blood-brain barrier (BBB) disruption remains unknown. This study aimed to investigate the role and underlying mechanism of ATM in the regulation of the BBB function in sepsis. ⋯ By activating ATM, doxorubicin increased the protein binding between ATM and AKT and promoted the phosphorylated activation of AKT at S473, which could directly phosphorylate DRP1 at S637 to repress excessive mitochondrial fission. Consistently, the protective role of ATM was abolished by the AKT inhibitor MK-2206. Conclusions: Ataxia telangiectasia mutated protects against LPS-induced BBB disruption by regulating mitochondrial homeostasis, at least in part, through the AKT/DRP1 pathway.
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During and immediately after cardiac arrest, cerebral oxygen delivery is impaired mainly by microthrombi and cerebral vasoconstriction. This may narrow capillaries so much that it might impede the flow of red blood cells and thus oxygen transport. The aim of this proof-of-concept study was to evaluate the effect of M101, an extracellular hemoglobin-based oxygen carrier (Hemarina SA, Morlaix, France) derived from Arenicola marina , applied during cardiac arrest in a rodent model, on markers of brain inflammation, brain damage, and regional cerebral oxygen saturation. ⋯ While M101 applied during cardiac arrest did not significantly change inflammation or brain oxygenation, the data suggest cerebral damage reduction due to hypoxic brain injury, measured by phospho-tau. Global burden of ischemia appeared reduced because acidosis was less severe. Whether postcardiac arrest infusion of M101 improves brain oxygenation is unknown and needs to be investigated.
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Introduction: Traumatic shock and hemorrhage (TSH) is a leading cause of preventable death in military and civilian populations. Using a TSH model, we compared plasma with whole blood (WB) as prehospital interventions, evaluating restoration of cerebral tissue oxygen saturation (CrSO 2 ), systemic hemodynamics, colloid osmotic pressure (COP) and arterial lactate, hypothesizing plasma would function in a noninferior capacity to WB, despite dilution of hemoglobin (Hgb). Methods: Ten anesthetized male rhesus macaques underwent TSH before randomization to receive a bolus of O(-) WB or AB(+) plasma at T0. ⋯ Peak lactate at T30 was significantly higher than baseline in both groups (WB 6.6 ± 4.9 vs. plasma 5.7 ± 1.6 mmol/L) declining equivalently by T60. Conclusions: Plasma restored hemodynamic support and CrSO 2 , in a capacity not inferior to WB, despite absence of additional Hgb supplementation. This was substantiated via return of physiologic COP levels, restoring oxygen delivery to microcirculation, demonstrating the complexity of restoring oxygenation from TSH beyond simply increasing oxygen carrying capacity.
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Introduction: Acute lung injury (ALI) is a devastating pulmonary illness with diffuse inflammatory responses. Hydromorphone (Hyd) is an opioid agonist used for relieving moderate-to-severe pain. The present work investigated the effect of Hyd on cardiopulmonary bypass (CPB)-induced ALI by regulating pyroptosis of alveolar macrophages (AMs). ⋯ Hyd upregulated Nrf2/HO-1 expression levels to repress NLRP3 inflammasome-mediated pyroptosis. Treatment of nigericin or ML385 counteracted the role of Hyd in ameliorating pyroptosis of AMs and CPB-induced ALI. Conclusions: Hyd alleviated NLRP3 inflammasome-mediated pyroptosis and CPB-induced ALI via upregulating the Nrf2/HO-1 pathway, which may be achieved by AMs.