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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We have demonstrated hemorrhagic shock "priming" for the development of indirect acute respiratory distress syndrome (iARDS) in mice following subsequent septic challenge, and show pathology characteristic of patients with iARDS, including increased lung microvascular permeability and arterial PO2/FI02 reduced to levels comparable to mild/moderate ARDS during the 48 h following hemorrhage. Loss of endothelial cell (EC) barrier function is a major component in the development of iARDS. EC growth factors, Angiopoietin (Ang)-1 and 2, maintain vascular homeostasis via tightly regulated competitive interaction with tyrosine kinase receptor, Tie2, expressed on ECs. ⋯ In this study we show that Ang-2 in lung tissue and plasma spikes following hemorrhage (priming) and remain elevated at sepsis induction. In addition, that transient inhibition of Ang-2 function immediately following hemorrhage, suppressing priming, but not following sepsis, impacts the development of iARDS in our model. Our data demonstrate that selective temporal blockade of Ang-2 function following hemorrhagic shock priming significantly improved PO2/FIO2, decreased lung protein leak and indices of inflammation, and improved 10-day survival in our murine model for the development iARDS.
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The inflammatory response is characterized by increased endothelial permeability, which permits the passage of fluid and inflammatory cells into interstitial spaces. The Eph/ephrin receptor ligand system plays a role in inflammation through a signaling cascade, which modifies Rho-GTPase activity. We hypothesized that blocking Eph/ephrin signaling using an EphA4-Fc would result in decreased inflammation and tissue injury in a model of ischemia/reperfusion (I/R) injury. ⋯ Finally, we confirmed the direct role of Eph/ephrin signaling in endothelial leakage by demonstrating that EphA4-Fc inhibited tumor necrosis factor-α-induced vascular permeability in human umbilical vein endothelial cells. This study identifies that Eph/ephrin interaction induces proinflammatory signaling in vivo by inducing vascular leak and neutrophil infiltration, which results in tissue injury in intestinal I/R. Therefore, therapeutic targeting of Eph/ephrin interaction using inhibitors, such as EphA4-Fc, may be a novel method to prevent tissue injury in acute inflammation by influencing endothelial integrity and by controlling vascular leak.
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Refrigeration of platelets (4°C) provides the possibility of improving transfusion practice over the current standard-of-care, room temperature (RT) storage. However, the increased level of platelet activation observed at 4°C in vitro is cause for concern of uncontrolled thrombosis in vivo. In this study, we assessed the safety of 4°C-stored platelets by evaluating their response to physiologic inhibitors prostacyclin (PGI2) and nitric oxide (NO). ⋯ While treatment with inhibitors did not attenuate thrombin generation in stored platelets, activation, aggregation, and adhesion responses were inhibited by both PGI2 and NO in 4°C-stored platelets. In contrast, though RT-stored platelets were activated, they did not adhere or aggregate in response to agonists. Thus, refrigerated platelets maintain their intracellular machinery, are responsive to agonists and platelet function inhibitors, and perform hemostatically better than RT-stored platelets.
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The intensity of continuous renal replacement therapy (CRRT) for acute kidney injury (AKI) has been evaluated, but recent randomized clinical trials have failed to demonstrate a beneficial impact of high intensity on the outcomes. High intensity might cause some detrimental results recognized recently as CRRT trauma. This study was undertaken to evaluate the association of CRRT intensity with mortality in a population of AKI patients treated with lower-intensity CRRT in Japan. ⋯ Overall, univariate Cox regression analysis indicated no association of the CRRT intensity with the 60-day in-hospital mortality rate (hazard ratio 1.006, 95% confidence interval [CI] 0.991-1.018, P = 0.343). In subanalysis with the septic AKI patients, multivariate analysis revealed two factors associated independently with the 60-day mortality rate: the Sequential Organ Failure Assessment score at initiation of CRRT (hazard ratio 1.152, 95% CI 1.025-1.301, P = 0.0171) and the CRRT intensity (hazard ratio 1.024, 95% CI 1.004-1.042, P = 0.0195). The CRRT intensity was associated significantly with higher 60-day in-hospital mortality in septic AKI, suggesting that unknown detrimental effects of CRRT with high-intensity CRRT might worsen the outcomes in septic AKI patients.
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Gastrointestinal barrier dysfunction is associated with the severity and prognosis of sepsis. Hydrogen gas (H2) can ameliorate multiple organ damage in septic animals. Ras homolog gene family member A (RhoA) and mammalian diaphanous-related formin 1 (mDia1) are important to regulate tight junction (TJ) and adherens junction (AJ), both of which determine the integrity of the intestinal barrier. ⋯ Rho inhibitor C3 exoenzyme mitigated LPS-induced barrier breakdown. Furthermore, H2-rich medium increased mDia1 expression, and mDia1 knockdown abolished protections of H2 on barrier permeability. mDia1 knockdown eliminated H2-induced benefits for occludin and E-cadherin. These findings suggest that H2 improves LPS-induced hyperpermeability of the intestinal barrier and disruptions of TJ and AJ by moderating RhoA-mDia1 signaling.