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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Approximately 3 billion people around the world have gone into some form of social separation to mitigate the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The uncontrolled influx of patients in need of emergency care has rapidly brought several national health systems to near-collapse with deadly consequences to those afflicted by Coronavirus Disease 2019 (COVID-19) and other critical diseases associated with COVID-19. Solid scientific evidence regarding SARS-CoV-2/COVID-19 remains scarce; there is an urgent need to expand our understanding of the SARS-CoV-2 pathophysiology to facilitate precise and targeted treatments. ⋯ Specifically, focus is given on SARS-CoV-2 immunopathogenesis in the context of experimental therapies and preclinical evidence and their applicability in supporting efficacious clinical trial planning. The review discusses the existing challenges of SARS-CoV-2 diagnostics and the potential application of translational technology for epidemiological predictions, patient monitoring, and treatment decision-making in COVID-19. Furthermore, solutions for enhancing international strategies in translational research, cooperative networks, and regulatory partnerships are contemplated.
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The world is currently embroiled in a pandemic of coronavirus disease 2019 (COVID-19), a respiratory illness caused by the novel betacoronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The severity of COVID-19 disease ranges from asymptomatic to fatal acute respiratory distress syndrome. In few patients, the disease undergoes phenotypic differentiation between 7 and 14 days of acute illness, either resulting in full recovery or symptom escalation. ⋯ Elevated IL-6 and hypoxia together predisposes patients to pulmonary hypertension, and the presence of asymptomatic hypoxia in COVID-19 further compounds this problem. Due to the similar downstream mediators, we discuss the potential synergistic effects and systemic ramifications of SARS-CoV-2 and influenza virus during co-infection, a phenomenon we have termed "COVI-Flu." Additionally, the differences between CRS and cytokine storm are highlighted. Finally, novel management approaches, clinical trials, and therapeutic strategies toward both SARS-CoV-2 and COVI-Flu infection are discussed, highlighting host response optimization and systemic inflammation reduction.
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Global cerebral ischemia-induced neuroinflammation causes neurofunctional impairment following cardiac arrest. Previous studies have demonstrated that the activation of protease-activated receptor-2 (PAR-2) contributes to neuroinflammation. In the present study, we aimed to determine the potential treatment effect of PAR-2 inhibition against neuroinflammation in the setting of asphyxial CA (ACA) in rats. ⋯ PAR-2 inhibition diminished neuroinflammation and thereby reduced hippocampal neuronal degeneration and neurocognitive impairment following ACA. This effect was at least partly mediated via the PAR-2/ERK1/2 signaling.
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The peptidylarginine deiminase (PAD) family converts arginine into citrulline through protein citrullination. PAD2 and PAD4 inhibitors can improve survival in hemorrhagic shock (HS). However, the impact of isoform-specific PAD inhibition in improving survival has not been studied. In this study, we utilize selective Pad2 knockout mice to elucidate loss of function of PAD2 leads to pro-survival effect in HS. ⋯ Pad2 improves survival in lethal HS. Possible mechanisms by which loss of PAD2 function improves survival include the activation of cell survival pathways, improved tolerance of cardiac ischemia, and improved cardiac function during ischemia. PAD2 is promising as a future therapeutic target for the treatment of HS and cardiac ischemia.
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Intra-abdominal infection is the second most common cause of sepsis, and the mortality rate from abdominal sepsis remains high. High molecular weight (HMW) hyaluronic acid (HA) has been studied in sterile injury models as an anti-inflammatory and anti-permeability agent. This study evaluated the therapeutic effects of intraperitoneal HMW HA administration in mice with peritonitis-induced sepsis. ⋯ At 6 h after CLP, HA significantly decreased bacterial burden in the peritoneal lavage fluid. HMW HA administration significantly increased E coli bacterial phagocytosis by RAW264.7 cells in part through increased phosphorylation of ezrin/radixin/moesin, a known downstream target of CD44 (a HA receptor); ezrin inhibition abolished the enhanced phagocytosis by RAW264.7 cells induced by HA. Intraperitoneal administration of HMW HA had therapeutic effects against CLP-induced sepsis in terms of suppressing inflammation and increasing antimicrobial activity.