Mechanisms of exercise protection in ventilator-induced diaphragm dysfunction

呼吸机所致膈肌功能障碍的运动保护机制

• 批准号: 8637933
• 负责人: Scott K. Powers
• 金额: $ 43.69万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637933
• 关键词: Acute respiratory failure; Address; Alveolar; Animal Model; Animals; Antioxidants; Antisense Oligodeoxyribonucleotides; Antisense Oligonucleotides; Atrophic; Attenuated; Biological; Clinical; Critical Illness; Dependovirus; Development; Disuse Atrophy; Environmental air flow; Enzymes; Exercise; Foundations; Functional disorder; Gene Silencing; Glutathione; Goals; HSP72 protein; Heat shock proteins; Intervention; Lead; Life; Manganese Superoxide Dismutase; Mechanical ventilation; Mediating; Mitochondria; Molecular; Molecular Target; Morbidity - disease rate; Muscle; Muscle Fibers; Muscle Weakness; Patients; Phenotype; Play; Prevention; Prevention strategy; Production; Public Health; Pulmonary Gas Exchange; Reactive Oxygen Species; Respiratory Diaphragm; Respiratory Muscles; Role; SOD2 gene; Skeletal Muscle; Testing; Time; Training; Ventilator; Weaning; Work; drug development; innovation; mortality; novel; novel strategies; novel therapeutics; overexpression; prevent; public health relevance; research study; sedentary; stress protein; therapeutic development; tool

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

描述（由申请人提供）：在临床上使用机械通气（MV）来维持无法维持足够肺泡通气的患者的肺气交换。尽管MV通常是一种挽救生命的干预措施，但长时间的MV在呼吸机的“断奶”患者中引起了问题。尽管几个因素可能导致断奶，但弱的吸气肌肉（即隔膜）是一个主要因素。在这方面，MV导致diaphragmaticativative促进了diaphragm萎缩和收缩功能障碍的快速发展，该功能被称为呼吸机诱导的隔膜功能障碍（VIDD）。目前，负责VIDD的机制知之甚少，因此不存在临床治疗。我们最近发现，耐力运动训练会导致diaphragm肌适应和受保护的隔膜表型。负责这种运动引起的对VIDD的保护的细胞机制仍然未知，并且是该应用的重点。假设：在我们的初步实验的指导下，我们将检验以下假设：运动诱导的隔膜对VIDD的保护取决于：1）线粒体抗氧化剂的diaphragmatical水平升高（即锰超氧化物歧化酶（SOD2）和glutathione和glutathione and Spp72）和/2）hope protine and hack protein and hack protein and hack protine shack protein and Specnione 72。方法：我们的假设将使用已建立的MV动物模型进行检验。因果关系将使用创新的分子和药理学工具确定，以操纵SOD2，GSH和HSP72。具体目的：1）确定运动引起的对VIDD的保护是否需要增加隔膜肌纤维线粒体内的SOD2和/或谷胱甘肽的水平； 2）确定diaphragm中Hsp72的过表达是否需要进行锻炼引起的对VIDD的保护。意义：确定负责运动引起的膜片保护的机制将确定可以通过药理操纵的新型分子靶标，从而导致新的方法防止VIDD和减少MV断奶患者的问题。 1