Respiratory Muscle Weakness in Chronic Inflammation

描述（由申请人提供）：该项目的长期目标是确定在慢性炎症疾病（包括心力衰竭和慢性阻塞性肺疾病）中保持隔膜功能的治疗方法。我们目前的重点是膈肌的比力丧失，它会导致运动不耐受、呼吸困难和呼吸衰竭。肿瘤坏死因子（TNF）是一个很有前景的治疗靶点。慢性疾病患者血清TNF水平升高，与肌肉无力相关，是发病率和死亡率的预测因子。TNF抑制膈肌的收缩功能，刺激膈肌纤维产生氧化剂。氧化剂似乎造成虚弱，因为限制氧化活性的干预措施可以防止失去力量。我们的中心假设是，在慢性炎症疾病中，通过抑制TNF受体介导的对膈肌纤维的作用，可以保留呼吸肌功能。该项目将定义信号事件和氧化还原机制，通过TNF抑制力，并将评估药理学和遗传干预措施，以保持隔膜功能。我们还将评估病理生理学相关性，定义肿瘤坏死因子在疾病小鼠模型中的作用，并测试临床治疗药物保护隔膜功能的能力。该项目有三个具体目标：目标1。评估鞘脂信号作为TNF/TNFR1刺激氧化活性和虚弱的早期受体后机制。细胞培养研究将评估鞘磷脂酶激活和TNF受体亚型1下游的神经酰胺敏感信号事件。目标2。评估介导tnf刺激的衰弱的氧化剂的来源、组成和翻译后靶标。隔膜纤维束和分离的线粒体将通过氧化还原测定和药理学和遗传学工具来确定ROS和NO的贡献。目标3。测试TNF信号作为心力衰竭呼吸肌无力的一个因素和潜在的治疗靶点。心力衰竭的动物模型将用于确定膈膜对慢性炎症的反应，测试TNF作为全身介质，并评估批准用于人类的潜在治疗方法。公共卫生相关性：慢性炎症性疾病，包括心力衰竭和肺气肿，会削弱用于呼吸的肌肉。这会导致呼吸困难的感觉，降低运动耐受性，并可能导致呼吸衰竭。该项目的目标是确定新的治疗方法，以保持呼吸肌功能，以减少疾病和延长寿命。

DESCRIPTION (provided by applicant): The long-term goal of this project is to identify therapies that will preserve diaphragm function in chronic inflammatory conditions including heart failure and chronic obstructive pulmonary disease. Our current focus is loss of specific force in diaphragm which promotes exercise intolerance, breathlessness, and respiratory failure. A promising therapeutic target is tumor necrosis factor (TNF). TNF serum levels are elevated in chronic disease, correlate with muscle weakness, and are a predictor of morbidity and mortality. TNF depresses contractile function of diaphragm and stimulates oxidant production by diaphragm muscle fibers. The oxidants appear to cause weakness since interventions that limit oxidant activity prevent loss of force. Our central hypothesis is that respiratory muscle function can be preserved in chronic inflammatory disease by inhibiting TNF receptor-mediated effects on diaphragm muscle fibers. This project will define signaling events and redox mechanisms by which TNF depresses force and will evaluate pharmacologic and genetic interventions to preserve diaphragm function. We also will evaluate pathophysiologic relevance, defining the role of TNF in a mouse model of disease and testing the capacity of clinical therapeutic agents to preserve diaphragm function. The project addresses three specific aims: Aim 1. To evaluate sphingolipid signaling as an early post-receptor mechanism by which TNF/TNFR1 stimulates oxidant activity and weakness. Cell culture studies will assess sphingomyelinase activation and ceramide-sensitive signaling events downstream of the TNF receptor subtype 1. Aim 2. To assess the source, composition, and post-translational target of oxidants that mediate TNF-stimulated weakness. Diaphragm fiber bundles and isolated mitochondria will be used to define ROS and NO contributions via redox assays and pharmacologic and genetic tools. Aim 3. To test TNF signaling as a contributor to respiratory muscle weakness in heart failure and a potential target for therapy. An animal model of heart failure will be used to define the diaphragm response to chronic inflammation, to test TNF as a systemic mediator, and to evaluate potential therapies that are approved for use in humans. PUBLIC HEALTH RELEVANCE: Chronic inflammatory diseases, including heart failure and emphysema, weaken the muscles used for breathing. This promotes the debilitating sensation of breathlessness, decreases exercise tolerance, and can lead to respiratory failure. The goal of this project is to identify new therapies that preserve respiratory muscle function in order to lessen illness and prolong life.