Respiratory Muscle Weakness in Chronic Inflammation

描述(申请人提供)：该项目的长期目标是确定在包括心力衰竭和慢性阻塞性肺疾病在内的慢性炎症性疾病中保留隔膜功能的治疗方法。我们目前的重点是横隔膜的比力丧失，这会导致运动不耐受、呼吸困难和呼吸衰竭。肿瘤坏死因子(TNF)是一个很有前途的治疗靶点。肿瘤坏死因子血清水平在慢性病中升高，与肌肉无力相关，是发病率和死亡率的预测因子。肿瘤坏死因子抑制横隔肌的收缩功能，刺激横隔肌纤维产生氧化剂。氧化剂似乎造成了虚弱，因为限制氧化剂活性的干预措施防止了作用力的丧失。我们的中心假设是，在慢性炎症性疾病中，通过抑制肿瘤坏死因子受体对横隔肌纤维的影响，呼吸肌功能可以得到保护。该项目将定义信号事件和氧化还原机制，肿瘤坏死因子通过其抑制力量，并将评估药理学和遗传干预措施，以保持横隔膜的功能。我们还将评估病理生理学相关性，确定肿瘤坏死因子在小鼠疾病模型中的作用，并测试临床治疗药物保留横隔膜功能的能力。该项目致力于三个具体目标：目的1.评估鞘磷脂信号作为一种早期受体后机制，通过该机制，肿瘤坏死因子/肿瘤坏死因子受体1刺激氧化活性和弱点。细胞培养研究将评估鞘磷脂酶激活和神经酰胺敏感的信号事件的下游的肿瘤坏死因子受体亚型1。目的2。评估氧化剂的来源，组成和翻译后的目标，介导肿瘤坏死因子刺激的弱点。横隔膜纤维束和分离的线粒体将通过氧化还原分析以及药理学和遗传学工具来确定ROS和NO的贡献。目的3.检测肿瘤坏死因子信号在心力衰竭呼吸肌无力中的作用，并作为潜在的治疗靶点。心力衰竭的动物模型将被用来定义横隔膜对慢性炎症的反应，测试作为全身介质的肿瘤坏死因子，并评估被批准用于人类的潜在治疗方法。与公共卫生相关：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。这会加剧令人虚弱的气喘感，降低运动耐受性，并可能导致呼吸衰竭。该项目的目标是找到保护呼吸肌功能的新疗法，以减轻疾病和延长生命。

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.