Mechanisms of exercise protection in ventilator-induced diaphragm dysfunction

描述(申请人提供)：机械通气(MV)在临床上用于维持无法维持足够肺泡通气量的患者的肺气体交换。虽然机械通气通常是一种挽救生命的干预措施，但延长机械通气时间会导致患者在脱离呼吸机时出现问题。虽然有几个因素可能会导致脱机困难，但吸气肌(即横隔膜)薄弱是一个主要因素。在这一点上，MV导致横隔膜不活动，从而促进横隔肌萎缩和收缩功能障碍的快速发展，这被称为呼吸机诱导的横隔膜功能障碍(VIDD)。目前，对VIDD的发病机制(S)知之甚少，因此尚无临床治疗方法。我们最近发现耐力运动训练导致了横隔膜的适应性和预防VIDD的横隔膜表型。负责这种运动诱导的VIDD保护作用的细胞机制(S)仍不清楚，也是本应用的重点。假设：在我们的初步实验指导下，我们将检验这样的假设，即运动诱导的对VIDD的保护依赖于隔膜水平的增加：1)线粒体抗氧化剂(即锰超氧化物歧化酶(SOD2)和谷胱甘肽)和/或2)热休克蛋白72(HSP72)。方法：我们的假设将使用已建立的MV动物模型进行验证。将使用创新的分子和药理学工具来操纵隔膜内的SOD2、GSH和HSP72来确定因果关系。具体目的：1)确定运动诱导的对VIDD的保护是否需要增加横隔肌纤维线粒体中SOD2和/或谷胱甘肽的水平；以及2)确定HSP72在横隔膜的过度表达是否对于运动诱导的VIDD保护是必要的和充分的。意义：确定运动诱导的横隔膜保护机制(S)将确定可以在药理学上操纵的新的分子靶点，导致预防VIDD和减少撤机患者的MV问题的新方法。1

DESCRIPTION (provided by applicant): Mechanical ventilation (MV) is used clinically to sustain pulmonary gas exchange in patients that are incapable of maintaining adequate alveolar ventilation. Although MV is often a life- saving intervention, prolonged MV gives rise to problems in "weaning" patients from the ventilator. Although several factors can contribute to difficult weaning, weak inspiratory muscles (i.e., diaphragm) are a major factor. In this regard, MV results in diaphragmatic inactivity which promotes the rapid development of diaphragmatic atrophy and contractile dysfunction which is known as ventilator- induced diaphragm dysfunction (VIDD). At present, the mechanism(s) responsible for VIDD are poorly understood and thus, no clinical therapy exists. We recently discovered that endurance exercise training results in diaphragmatic adaptations and a diaphragm phenotype that is protected against VIDD. The cellular mechanism(s) responsible for this exercise-induced protection against VIDD remain unknown and are the focus of this application. HYPOTHESIS: Guided by our preliminary experiments, we will test the hypothesis that exercise- induced protection of the diaphragm against VIDD is dependent on increased diaphragmatic levels of: 1) mitochondrial antioxidants (i.e., manganese superoxide dismutase (SOD2) and glutathione) and/or 2) heat shock protein 72 (HSP72). APPROACH: Our hypothesis will be tested using an established animal model of MV. Cause and effect will be determined using innovative molecular and pharmacological tools to manipulate SOD2, GSH, and HSP72 within the diaphragm. SPECIFIC AIMS: 1) To determine if exercise-induced protection against VIDD requires increased levels of SOD2 and/or glutathione within mitochondria of diaphragm muscle fibers; and 2) To establish if overexpression of HSP72 in the diaphragm is necessary and sufficient for exercise-induced protection against VIDD. SIGNIFICANCE: Determining the mechanism(s) responsible for exercise-induced protection of the diaphragm will identify novel molecular targets that can be manipulated pharmacologically, leading to new approaches to prevent VIDD and reduce problems in weaning patients from MV. 1