The injurious effects of hypercapnia on the alveolar epithelium

高碳酸血症对肺泡上皮的损伤作用

• 批准号: 7256236
• 负责人: Jacob I Sznajder
• 金额: $ 44.03万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256236
• 关键词: Acidosis; Adult Respiratory Distress Syndrome; Affect; Alveolar; Animal Model; Apical; C. elegans genome; Caenorhabditis elegans; Carbon Dioxide; Cell membrane; Chronic; Chronic Obstructive Airway Disease; Collection; Data; Development; Disease; Down-Regulation; Edema; Elevation; Endocytosis; Environmental air flow; Epithelial; Epithelial Cells; Epithelium; Exposure to; Fertility; Functional disorder; Gases; Gene Targeting; Genes; Genetic; Genetic Screening; Hypercapnia; Impairment; Liquid substance; Locomotion; Lung; Lung diseases; MAPK8 gene; Maps; Measures; Mediating; Modeling; Mutate; Na(+)-K(+)-Exchanging ATPase; Numbers; Outcome; Pathway interactions; Patients; Phosphorylation; Protein Kinase C; Proteins; Pulmonary Edema; Pulmonary Gas Exchange; Regulation; Reporting; Research Personnel; Respiratory Failure; Rodent; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Ubiquitin; Ubiquitination; Universities; Ventilator-induced lung injury; Visit; Water; alveolar epithelium; base; cell motility; clinically relevant; day; injured; insight; lung injury; multicatalytic endopeptidase complex; novel; professor; programs; protein kinase C kinase; research study; response; sensor

DESCRIPTION (provided by applicant): Patients with COPD and mechanically ventilated patients with "permissive hypercapnia" can have significant elevation of pCO2. We hypothesize that hypercapnia causes dysfunction of the alveolar epithelium by specifically downregulating the alveolar epithelial Na,K-ATPase and decreasing alveolar fluid clearance. The focus of this application is to determine whether short term (30-60 min) hypercapnia impairs reversibly alveolar fluid reabsorption by inhibiting the Na,K-ATPase and promoting its endocytosis from the plasma membrane into intracellular compartments via specific pathways involving JNK and ERK kinases and protein kinase C (PKC) signaling molecules. We also propose to determine whether long term (5 and 7 days) hypercapnia sensitizes the alveolar epithelium to ventilation induced lung injury and causes not only endocytosis but degradation of the Na,K-ATPase via the ubiquitin/proteosome pathway. The cellular signals that sense hypercapnia are largely unknown, therefore we will take advantage that the genome of C. Elegans has been completely mapped and conduct experiments in C. elegans to study potential genes that may participate in the sensing and response to high pCO2. As such, we will study the effects of hypercapnia on the alveolar epithelium and C. elegans via four interrelated aims: in Specific Aim 1 we propose to determine whether hypercapnia decreases alveolar fluid reabsorption in normal and injured lungs and whether these effects are due to high pCO2 or the associated acidosis, in Specific Aim 2 we will determine the signaling pathways by which hypercapnia promotes alveolar epithelial Na,K-ATPase endocytosis in alveolar epithelial cells , in Specific Aim 3 we will determine whether hypercapnia inhibits Na,K-ATPase activity via phosphorylation and ubiquitination leading to the endocytosis and degradation of Na,K-ATPase proteins and in Specific Aim 4 we will determine the effect of elevated levels of CO2 on C. elegans development, motility and fertility and establish a collection of lines mutated in genes that regulate the sensing and cellular response to elevated levels of CO2. Experiments have been conducted for each of the specific aims and the preliminary results support the feasibility of this proposal. Completion of the proposed studies will provide novel information on the effects of hypercapnia on the alveolar epithelium, specifically as it pertains to mechanisms of alveolar epithelial barrier dysfunction which may be of importance for the treatment of hypercapnic patients.

描述（由申请人提供）：患有COPD和机械通风的患者“允许性高碳酸盐”患者可以显着升高PCO2。我们假设高碳酸血症会通过特别下调肺泡上皮Na，K-ATPase并降低肺泡液清除率，从而引起肺泡上皮的功能障碍。该应用的重点是确定短期（30-60分钟）过度capnia是否通过抑制Na，K-ATPase并通过涉及JNK和Erk Kinasse cimein kinase cycles（pkc）的特定途径来抑制Na，K-ATPase并促进其从质膜进入细胞内室内的内吞作用，从而损害可逆性肺泡液的吸收。我们还建议确定长期（5天和7天）过度capnia是否使肺泡上皮敏感到通气诱导的肺损伤，不仅会导致内吞作用，而且会导致Na，K-ATPase通过泛素/蛋白质组途径降解。理性高碳酸盐的细胞信号在很大程度上是未知的，因此，我们将利用秀丽隐杆线虫的基因组被完全映射，并在秀丽隐杆线虫中进行实验，以研究可能参与对高PCO2的感应和反应的潜在基因。因此，我们将通过四个相互关联的目的研究高碳酸脂蛋白对肺泡上皮和秀丽隐杆线虫的影响：在特定目的1中，我们建议确定高碳水化合物是否会降低肺泡液在正常和受伤的肺中是否会吸收肺泡液在肺中的肺泡吸收，而这些影响是否会促进PCO2或相关的酸性途径2，这是通过特定的酸性促进的，而高度co的信号却是高度co，而高速公路则是高度co，而高速公路则是高速公路2。 Na，K-ATPase内吞作用在肺泡上皮细胞中，在特定的目的3中，我们将通过磷酸化和泛素化来抑制Na，K-ATPase活性，导致Na，K-ATP酶蛋白质的内吞作用和降解，K-ATPase蛋白和特定目标4的效果，我们将确定C. conty and coct of C.2 co的效应。在调节二氧化碳水平升高的传感和细胞反应的基因中。已经针对每个特定目的进行了实验，初步结果支持该提案的可行性。拟议研究的完成将提供有关高碳酸脂蛋白对牙槽上皮的影响的新信息，特别是与肺泡上皮屏障功能障碍的机制有关，这对于治疗高碳酸含量患者可能很重要。