Mechanical Ventilation and Diaphragmatic Oxidant Injury

机械通气和膈肌氧化损伤

• 批准号: 7417491
• 负责人: Scott K. Powers
• 金额: $ 31.04万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7417491
• 关键词: Alveolar; Animal Model; Animals; Antioxidants; Atrophic; Attenuated; Binding; Biochemical Pathway; Cells; Chelating Agents; Clinical; Coupling; Data; Depressed mood; Elements; Environmental air flow; Functional disorder; Generations; Heme; Hydroxyl Radical; Injury; Iron; Lipids; Measures; Mechanical ventilation; Modeling; Muscle; Muscle Weakness; Muscular Atrophy; NAD(P)H oxidase; Nitric Oxide; Nitric Oxide Synthase; Numbers; Oxidants; Oxidases; Oxidative Stress; Oxygenases; Pathway interactions; Patients; Process; Production; Proteins; Proteolysis; Pulmonary Gas Exchange; Rattus; Reactive Oxygen Species; Relative (related person); Reporting; Respiratory Diaphragm; Skeletal Muscle; Source; Stress; Superoxides; Techniques; Testing; Weaning; Withdrawal; Work; Xanthine Oxidase; Xanthines; base; design; experience; inhibitor/antagonist; innovation; oxidation; prevent; protein function; research study; xanthine

DESCRIPTION (provided by applicant): Mechanical ventilation (MV) is used to sustain pulmonary gas exchange in patients incapable of maintaining adequate alveolar ventilation. The withdrawal of MV from patients is called "weaning" and problems in weaning are frequent. Studies reveal that diaphragmatic weakness is a key contributor to weaning difficulties. Importantly, we have discovered that MV-induced diaphragmatic weakness is associated with oxidative damage to the diaphragm. Moreover, our recent work reveals that MV-induced oxidative stress depresses diaphragmatic specific force production and promotes proteolysis leading to diaphragmatic atrophy. At present, the mechanism(s) responsible for MV-induced production of cellular oxidants are unknown. Therefore, these experiments will determine the oxidant pathway(s) responsible for MV-induced oxidative injury in the diaphragm. Based upon preliminary experiments, our working hypothesis is that MVinduced diaphragmatic oxidative stress occurs due to interactions between 4 oxidant-producing pathways: 1) production of superoxide radicals by NAD(P)H oxidase; 2) generation of superoxide radicals by the xanthine oxidase pathway; 3) nitric oxide production via nitric oxide synthase; and 4) formation of hydroxyl radicals by increased cellular levels of reactive iron. This hypothesis will be tested in a rat model of MV using an innovative and comprehensive experimental approach. First, we will measure MV-induced oxidative injury in the diaphragm using a panel of established techniques. Secondly, we will investigate critical elements of each oxidant production pathway to determine if these components are elevated in diaphragms from MV animals. Further, we will employ proven pharmacological inhibitors of each oxidant pathway to determine the relative importance of the pathway in MV-induced diaphragmatic oxidative injury and contractile dysfunction. Delineating the biochemical pathways responsible for MV-induced oxidant production in the diaphragm is essential to developing an effective approach to oppose this damaging process. These experiments will provide new and important mechanistic information about the source of oxidants in the diaphragm that can be used to develop optimal clinical strategies to retard MV-induced diaphragmatic oxidant stress and contractile dysfunction.

描述（由申请人提供）：机械通气（MV）用于维持无法维持足够肺泡通气的患者的肺气交换。从患者中撤出MV称为“断奶”，断奶中的问题经常出现。研究表明，隔膜弱点是断奶困难的关键因素。重要的是，我们发现MV诱导的diaphragm肌无力与对隔膜的氧化损伤有关。此外，我们最近的工作表明，MV诱导的氧化应激降低了diaphragmagmatic的特异性力的产生，并促进蛋白水解导致diaphragmantagy萎缩。目前，负责MV诱导的细胞氧化剂产生的机制尚不清楚。因此，这些实验将确定负责MV诱导的氧化损伤的氧化途径。基于初步实验，我们的工作假设是，由于4种产生氧化剂的途径之间的相互作用，M v诱导的diaphragmagragm氧化应激发生：1）NAD（p）H氧化酶生产超氧化物自由基； 2）黄嘌呤氧化酶途径产生超氧化物自由基； 3）一氧化氮通过一氧化氮合酶产生； 4）由反应性铁的细胞水平增加形成羟基自由基。该假设将使用创新和全面的实验方法在MV的大鼠模型中进行检验。首先，我们将使用一系列已建立技术来测量MV诱导的膜片氧化损伤。其次，我们将研究每种氧化剂生产途径的关键元素，以确定MV动物的隔膜中这些成分是否升高。此外，我们将采用每种氧化剂途径的经过验证的药理抑制剂来确定该途径在MV诱导的diaphragmapmapmamatic氧化损伤和收缩功能障碍中的相对重要性。描述负责MV诱导的隔膜氧化剂产生的生化途径对于开发一种有效的方法来反对这一有害过程至关重要。这些实验将提供有关隔膜中氧化剂来源的新的重要机械信息，这些信息可用于开发最佳的临床策略，以阻止MV诱导的diaphragmagmantagragmantagragmantial diaphragmaragmantagication diaphragmagmatic氧化剂应激和收缩功能障碍。

项目成果

Increased temperature and protein oxidation lead to HSP72 mRNA and protein accumulation in the in vivo exercised rat heart.

温度升高和蛋白质氧化导致 HSP72 mRNA 和蛋白质在体内运动的大鼠心脏中积累。

• DOI: 10.1113/expphysiol.2008.044685
• 发表时间: 2009
• 期刊: Experimental physiology
• 影响因子: 2.7
• 作者: Staib,JessicaL;Tümer,Nihal;Powers,ScottK
• 通讯作者: Powers,ScottK

Can antioxidants protect against disuse muscle atrophy?

• DOI: 10.1007/s40279-014-0255-x
• 发表时间: 2014-11
• 期刊: Sports medicine (Auckland, N.Z.)
• 作者: Powers SK

Mechanical ventilation induces diaphragmatic mitochondrial dysfunction and increased oxidant production.

• DOI: 10.1016/j.freeradbiomed.2009.01.002
• 发表时间: 2009-03-15
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Kavazis, Andreas N.;Talbert, Erin E.;Smuder, Ashley J.;Hudson, Matthew B.;Nelson, W. Bradley;Powers, Scott K.
• 通讯作者: Powers, Scott K.

Overexpression of antioxidant enzymes in diaphragm muscle does not alter contraction-induced fatigue or recovery.

• DOI: 10.1113/expphysiol.2009.049650
• 发表时间: 2010-01
• 期刊: Experimental physiology
• 影响因子: 2.7
• 作者: McClung JM;Deruisseau KC;Whidden MA;Van Remmen H;Richardson A;Song W;Vrabas IS;Powers SK
• 通讯作者: Powers SK

Both high level pressure support ventilation and controlled mechanical ventilation induce diaphragm dysfunction and atrophy.

• DOI: 10.1097/ccm.0b013e31823c8cc9
• 发表时间: 2012-04
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Hudson MB;Smuder AJ;Nelson WB;Bruells CS;Levine S;Powers SK
• 通讯作者: Powers SK