Redox regulation of alveolar fluid balance

肺泡液平衡的氧化还原调节

• 批准号: 7450433
• 负责人: My N. Helms
• 金额: $ 8.91万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7450433
• 关键词: AGTR2 gene; Alveolar; Alveolar Cell; Alveolus; Amiloride; Apical; Binding; Biological Assay; Biological Models; Breathing; Cell Death; Cells; Complex; Condition; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Environment; Epithelial Cells; Epithelium; Equilibrium; Fatigue; Fluid Balance; Gases; Genes; Goals; Homeostasis; Ion Channel; Ion Transport; Lead; Length; Life; Liquid substance; Lung; Measurement; Measures; Mentors; Methods; Modeling; Molecular; Mus; Nitric Oxide; Oxidation-Reduction; Oxygen; Oxygen measurement, partial pressure, arterial; Peroxonitrite; Phase; Physiological; Play; Preparation; Production; Property; Protocols documentation; Rattus; Reactive Nitrogen Species; Reactive Oxygen Species; Regulation; Research; Research Design; Research Personnel; Respiratory physiology; Role; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Slice; Small Interfering RNA; Sodium Chloride; Superoxide Dismutase; Superoxides; Surface; Techniques; Testing; Time; Tissues; Transgenic Mice; Water; Work; alveolar epithelium; career; cell type; clinically relevant; epithelial Na+ channel; epithelial amiloride-sensitive sodium channel; human NOS2A protein; in vivo; in vivo Model; inhibitor/antagonist; insight; novel strategies; patch clamp; pneumocyte; programs

DESCRIPTION (provided by applicant): The alveolar epithelium in normal lungs is comprised of two morphologically distinct types of cells (type 1 and type 2) that are responsible for maintaining lung fluid balance. Tight regulation of alveolar fluid clearance is essential for maintaining a dry breathing space, and hence, proper gas exchange. It has been established that net ion transport through amiloride-sensitive epithelial sodium channels (ENaC), located on the apical surface of alveolar epithelial cells, play a critical role in fluid clearance in normal lung. However, the specific mechanisms regulating ENaC function are not completely understood. Within the alveoli, complex regulatory mechanisms must also be in place to balance the redox state of type 1 and type 2 cells, since inspired oxygen is converted to superoxide anions (O2-). Excessive O2- production, caused by high oxygen tensions, can lead to tissue damage and cell death, whereas insufficient oxygenation can result in anything from fatigue to life threatening conditions. In vivo, superoxides react quickly and irreversibly with nitric oxide (NO) to form peroxynitrite. We hypothesize that endogenous 02- binding to NO limits nitric oxide inhibition of ENaC function, thereby enhancing alveolar fluid clearance. Indeed, we have preliminary data suggesting that nitric oxide-unresponsive AT1 cells may have elevated levels of O2-, and that increasing O2- enhances Na transport. To investigate the role of redox signaling in alveolar fluid clearance, and more specifically, ENaC function, I will utilize single channel patch clamp analysis to examine ion transport in lung slice preparations, bio-molecular techniques to examine redox signaling in pneumocytes, and perform whole lung studies in vivo. My first aim, performed during the mentored phase, directly examines the role of O2- in alveolar fluid clearance. Successful completion of this aim will naturally transition into aims 2 and 3, which utilizes several protocols that will be established in the mentored phase, as well as incorporate new approaches to studying type 1 and type 2 cells. The second aim will determine the role of NO in lung function, and lastly, the third aim examines the putative reciprocal relationship between O2- and NO regulation of lung fluid balance. The studies proposed have real clinical relevance, and the potential for a very productive independent research career.

描述（由申请人提供）：