Respiratory Muscle Weakness

呼吸肌无力

基本信息

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
项目类别：
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

项目摘要

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，危重患者的膈肌变得非常脆弱。反过来，膈肌无力会增加机械通气的持续时间，增加患者死亡率，并且是 VA 医疗保健系统中照顾危重机械通气患者的高昂费用的主要原因。我们自己的工作表明，感染是危重患者出现严重膈肌无力的主要原因。还已知感染会引起膈肌自由基生成的增加，而自由基生成的增加会导致虚弱的发展。然而，感染激活骨骼肌中自由基产生的确切机制尚不清楚。此外，目前还没有药物治疗可以预防或逆转危重患者感染引起的膈肌无力。本项目的目的是发现感染增加膈肌自由生成的机制，并利用这一机制信息来定义新的可转化药物治疗，可用于预防和逆转危重患者的膈肌无力。我们的中心假设是，感染引起的膈肌功能障碍主要是中性鞘磷脂酶 2、胞质磷脂酶 A2 (cPLA2)、线粒体自由基生成和蛋白水解途径（例如钙蛋白酶）相继激活的结果。计划中的研究将测试这一假设，并利用这些信息来定义可以快速转化为临床应用的新疗法。目标 1 实验将描述感染诱导骨骼肌中自由基生成增加的具体机制。实验 1.1 将检验以下假设：感染首先激活骨骼肌中的中性鞘磷脂酶 2。实验 1.2 将检验以下假设：感染诱导的中性鞘磷脂酶 2 激活随后激活骨骼肌 cPLA2，进而诱导线粒体自由基产生增加。目标 2 实验将确定由于感染诱导 cPLA2 激活和线粒体自由基生成而激活的特定骨骼肌蛋白水解途径（实验 2.1）和细胞蛋白降解（实验 2.2）。目标 3 实验将确定阻断 cPLA2 激活和线粒体自由基生成的新型药物是否可以防止脓毒症盲肠结扎穿孔动物模型中膈肌功能的丧失。我们将在实验 3.1 中研究一种阻断 cPLA2（牛磺酸）激活的药物，在实验 3.2 中研究一种直接 cPLA2 抑制剂 (CDIBA)，在实验 3.3 中研究一种线粒体自由基生成抑制剂 (SS31)。