Mechanisms of exercise protection in ventilator-induced diaphragm dysfunction

描述（由申请人提供）：机械通气（MV）在临床上用于不能维持足够肺泡通气的患者维持肺气体交换。虽然中压通气通常是一种挽救生命的干预措施，但长时间的中压通气会给“脱离”呼吸机的患者带来问题。虽然有几个因素会导致难以脱机，但无力的吸气肌（即膈肌）是一个主要因素。在这方面，中压导致膈肌不活动，从而促进膈肌萎缩和收缩功能障碍的快速发展，即呼吸机诱发的膈肌功能障碍（VIDD）。目前，VIDD的发病机制尚不清楚，因此尚无临床治疗方法。我们最近发现，耐力运动训练导致横膈膜适应和横膈膜表型，以防止VIDD。负责这种运动诱导的抗VIDD保护的细胞机制仍然未知，是本应用的重点。假设：在我们初步实验的指导下，我们将验证运动诱导的膈肌抗VIDD保护依赖于膈肌水平增加的假设：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动物模型进行验证。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)确定运动诱导的抗VIDD保护是否需要膈肌纤维线粒体中SOD2和/或谷胱甘肽水平的增加；2)确定HSP72在横膈膜中的过表达对于运动诱导的抗VIDD保护是否必要和充分。意义：确定运动诱导膈肌保护的机制将确定新的分子靶点，这些靶点可以在药理学上进行操纵，从而为预防VIDD和减少脱机MV患者的问题提供新的方法。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