Mitochondrially Targeted Therapies for Sepsis Induced Diaphragm Dysfunction

大多数机械通气的MICU患者存在严重的获得性隔膜功能障碍 病人。重要的是，最近的研究表明，横隔膜薄弱的患者有更长的 需要机械通风，死亡率明显较高。因此，增加的治疗方法 横隔膜功能有可能改善MICU患者的预后。这些最近的研究还表明 ICU获得性隔膜无力的主要危险因素是感染。感染导致显著增加 在横隔膜中，线粒体产生自由基，而这些自由基有助于虚弱和 疲惫。因此，目前的提议将检验药物疗法的假设 旨在抑制线粒体自由基生成或诱导线粒体修复 预防和/或逆转败血症引起的横隔膜功能障碍。这一理论将在四年内得到检验 研究小组： 目的1研究将验证脓毒症引起的隔膜功能障碍可以通过以下方法减少的假说 抑制线粒体自由基的药物。实验将采用盲肠结扎穿刺术进行脓毒症 模型(CLP)比较假手术、CLP、CLP加药、假加药的隔膜功能 组。接受测试的药物包括MitoTEMPOL、SKQ1和Necrostatin。 目的2项研究将检验以下假设：给予线粒体生物发生激活剂可以 改善感染引起的横隔膜功能障碍。中电将再次引发败血症，我们将 检查三种治疗方法(即AICAR+PQQ、PQQ和AICAR+GW1506)预防CLP的能力 诱发的横隔膜功能障碍。 目标3研究将评估目标1和目标2药物产生影响的机制。 肌肉细胞。这些实验还将检验这些药物诱导肌动蛋白释放的假设。 它们具有自分泌作用，可减轻细胞因子诱导的肌细胞损伤。 目的4项研究将检验肌细胞因子给药可作为一种药理作用的假设。 减轻脓毒症引起的动物横隔膜功能障碍的治疗。待检测的肌动蛋白包括虹膜蛋白 和其他在AIM 3研究中发现的蛋白质，可以在体外阻断细胞因子诱导的肌肉细胞损伤。

Severe ICU acquired diaphragm dysfunction is present in the majority of mechanically ventilated MICU patients. Importantly, recent work indicates that patients with weak diaphragms have a much longer requirement for mechanical ventilation and a markedly higher mortality. As a result, therapies that increase diaphragm function have the potential to improve MICU patient outcomes. These recent studies also suggest that a major risk factor for ICU acquired diaphragm weakness is infection. Infections elicit a marked increase in diaphragm mitochondrial free radical production, and these free radicals contribute to weakness and fatigue. The present proposal, therefore, will test the hypothesis that pharmacological therapies designed to either inhibit mitochondrial free radical generation or induce mitochondrial repair will prevent and/or reverse sepsis mediated diaphragm dysfunction. This theory will be tested in four groups of studies: Aim 1 studies will test the hypothesis that sepsis induced diaphragm dysfunction can be reduced by using agents which inhibit mitochondrial free radicals. Experiments will utilize the cecal ligation puncture sepsis model (CLP) and compare diaphragm function in sham operated, CLP, CLP plus drug, and sham plus drug groups. Drugs to be tested include mitoTEMPOL, SKQ1, and necrostatin. Aim 2 studies will test the hypothesis that administration of activators of mitochondrial biogenesis can improve infection induced diaphragm dysfunction. Sepsis will again be produced with CLP and we will examine the ability of three treatments (i.e. AICAR+PQQ, PQQ, and AICAR+GW1506) to prevent CLP induced diaphragm dysfunction. Aim 3 studies will evaluate the mechanisms by which Aim 1 and Aim 2 drugs produce their effects on muscle cells. These experiments will also test the hypothesis that these agents induce release of myokines which have autocrine effects to attenuate cytokine induced muscle cell damage. Aim 4 studies will test the hypothesis that myokine administration can be used as a pharmacological treatment to attenuate sepsis induced diaphragm dysfunction in animals. Myokines to be tested include irisin and other proteins found in Aim 3 studies to block cytokine induced muscle cell damage in vitro.