Respiratory Muscle Weakness

呼吸肌无力

• 批准号: 9280803
• 负责人: GERALD S. SUPINSKI
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280803
• 关键词: Adrenal Cortex Hormones; Animal Model; Animals; Biophysical Process; Calpain; Caspase; Clinical; Contractile Proteins; Critical Care; Critical Illness; Cytosolic Phospholipase A2; Development; Free Radicals; Functional disorder; Generations; Goals; Healthcare Systems; Human; Hyperglycemia; Infection; Interferons; Interleukin-1; Ligation; Mechanical Ventilators; Mechanical ventilation; Mechanics; Mediating; Mitochondria; Muscle; Muscle Weakness; Muscle function; Myosin Heavy Chains; Pathway interactions; Patients; Perforation; Pharmacological Treatment; Pharmacology; Production; Proteins; Proteolysis; Respiration; Respiratory Diaphragm; Respiratory Failure; Respiratory Muscles; Risk Factors; Sepsis; Skeletal Muscle; Spectrin; Sphingomyelinase; TNF gene; Talin; Taurine; Testing; Translating; Weaning; Work; base; cost; cytokine; disability; experimental study; improved; inhibitor/antagonist; mortality; multicatalytic endopeptidase complex; muscle strength; novel; novel therapeutics; patient population; prevent; public health relevance

DESCRIPTION (provided by applicant): Recent studies indicate that the diaphragm becomes profoundly weak in critically ill patients. Diaphragm weakness, in turn, increases the duration of mechanical ventilation, increases patient mortality, and is a major contributor to the high cost of taking care of critically ill, mechanically ventilated patients in the VA health care system. Our own work indicates that infections are a major cause of the development of severe diaphragm weakness in critically ill patients. It is also known that infections elicit increases in diaphragm free radical generation, and that heightened free radical generation contributes to the development of weakness. The precise mechanism(s) by which infections activate free radical generation in skeletal muscle are not known, however. Moreover, currently there is no pharmacological treatment to prevent or reverse infection induced diaphragm weakness in critically ill patients. The purpose of the present project is to discover the mechanisms by which infections increase diaphragm free generation and to employ this mechanistic information to define novel translatable pharmacological treatments that can be used to prevent and reverse diaphragm weakness in critically patients. Our central hypothesis is that infection induced diaphragm dysfunction is primarily a consequence of the sequential activation of neutral sphingomyelinase 2, cytosolic phospholipase A2 (cPLA2), mitochondrial free radical generation, and proteolytic pathways (e.g. calpain). The planned studies will test this hypothesis and use this information to define new therapies that can be quickly translated into clinical usage. Aim 1 experiments will delineate the specific mechanism(s) by which infections induce heightened free radical generation in skeletal muscle. Experiment 1.1 will test the hypothesis that infections first activate neutral sphingomyelinase 2 in skeletal muscle. Experiment 1.2 will test the hypothesis that infection induced activation of neutral sphingomyelinase 2 subsequently activates skeletal muscle cPLA2, which, in turn, induces an increase in mitochondrial free radical production. Aim 2 experiments will determine the specific skeletal muscle proteolytic pathways activated (Experiment 2.1) and cellular proteins degraded (Experiment 2.2) as a consequence of infection induced activation of cPLA2 and mitochondrial free radical generation. Aim 3 experiments will determine if novel pharmacological agents which block cPLA2 activation and mitochondrial free radical generation prevent loss of diaphragm function in the cecal ligation perforation animal model of sepsis. We will study an agent which blocks activation of cPLA2 (taurine) in Experiment 3.1, a direct cPLA2 inhibitor (CDIBA) in Experiment 3.2, and an inhibitor of mitochondrial free radical generation (SS31) in Experiment 3.3.

描述（由申请人提供）： 最近的研究表明，在危重患者中，隔膜变得非常弱。反过来，隔膜无力增加了机械通气的持续时间，增加了患者的死亡率，并且是VA卫生保健系统中严重生病，机械通风的患者的高成本的主要贡献者。我们自己的工作表明，感染是重症患者严重隔膜弱点发展的主要原因。众所周知，感染引起的隔膜自由基产生增加，而自由基的增强产生有助于弱点的发展。然而，感染激活骨骼肌自由基产生的精确机制尚不清楚。此外，目前尚无药物治疗可预防或逆转感染引起的膜片弱点。本项目的目的是发现感染增加无隔膜的机制，并采用这种机械信息来定义可翻译的新型药理治疗方法，这些治疗方法可用于预防和反向诊断患者的膜片弱点。 我们的中心假设是，感染引起的隔膜功能障碍主要是中性鞘磷脂酶2，胞质磷脂酶A2（CPLA2），线粒体自由基自由基生成和蛋白水解途径的顺序激活的结果。计划的研究将检验这一假设，并使用此信息来定义可以快速转化为临床用法的新疗法。 AIM 1实验将描绘 特定机制通过感染引起骨骼肌的自由基产生增强。实验1.1将检验以下假设：感染首先在骨骼肌中激活中性鞘磷脂酶2。实验1.2将检验以下假设：感染诱导中性鞘磷脂酶2的激活随后激活骨骼肌CPLA2，这反过来又诱导了线粒体自由基生产的增加。 AIM 2实验将确定激活的特定骨骼肌蛋白水解途径（实验2.1）和由于感染引起的CPLA2激活CPLA2和线粒体自由基的激活而降解的细胞蛋白（实验2.2）。 AIM 3实验将确定阻塞CPLA2激活和线粒体自由基产生的新型药理学剂是否在败血症的盲肠连接穿孔动物模型中丧失了diaphragm的功能。我们将研究一种试剂，该试剂阻止实验3.1中CPLA2（牛磺酸）的激活，实验3.2中直接的CPLA2抑制剂（CDIBA），以及实验3.3中线粒体自由基（SS31）的抑制剂。