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: 8584306
• 负责人: Jacob I Sznajder
• 金额: $ 38.42万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584306
• 关键词: Acute Lung Injury; Adenylate Cyclase; Adult Respiratory Distress Syndrome; Alveolar; Animal Model; Animals; Apical; Applications Grants; Award; Blood; Caenorhabditis elegans; Carbon Dioxide; Cell membrane; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Disease; Down-Regulation; Endocytosis; Enzymes; Epithelial; Epithelial Cells; Functional disorder; Gases; Goals; Grant; Hypercapnia; Impairment; Injury; Intervention; LIM Domain; Lead; Light; Liquid substance; Lung; MAPK8 gene; Measures; Mechanical ventilation; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Na(+)-K(+)-Exchanging ATPase; Outcome; Pathway interactions; Patients; Phosphorylation; Process; Proteins; Pulmonary Edema; Rattus; Regulation; Reporting; Research; Research Personnel; Respiratory Failure; Rodent; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Ubiquitin; Ubiquitination; Ventilator-induced lung injury; alveolar epithelium; base; insight; multicatalytic endopeptidase complex; novel; novel strategies; public health relevance; research study; response; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): High pCO2 levels are observed in patients with respiratory failure ventilated with the "permissive hypercapnia" strategy. We and other investigators have recently reported that elevated pCO2 levels can have deleterious effects on the alveolar epithelium. Specifically, we have reported that hypercapnia leads to short and long term dysfunction of the alveolar epithelium by inhibiting the alveolar epithelial Na,K-ATPase and impairing alveolar fluid clearance. Therefore, the focus of this application is to determine the specific mechanisms/signaling pathways that lead to alveolar Na,K-ATPase downregulation and impairment in alveolar fluid clearance during hypercapnic conditions. We propose to study the effects of hypercapnia on the alveolar epithelium via four interrelated aims: in experiments pertaining to specific Aim # 1, we will determine whether the soluble adenylyl cyclase participates in the hypercapnia-induced Na,K- ATPase downregulation in the alveolar epithelium; in experiments pertaining to specific Aim #2, we will determine whether hypercapnia-induced JNK activation leads to LIM-domain only protein 7 (LMO7) phosphorylation and Na,K-ATPase endocytosis; in studies pertaining to specific Aim # 3, we will determine whether Na,K-ATPase ubiquitination leads to its downregulation and propose to identify the specific E2 and E3 ubiquitin ligase; and in studies pertaining to specific Aim # 4, we will determine whether hypercapnia further impairs injury in a model of mild ventilator-induced lung injury (VILI) and whether the downregulation of of sAC, JNK, LMO7 and ubiquitination pathway will reverse the deleterious effects of hypercapnia on alveolar fluid clearance in rodents. In the first cycle of this grant, we have completed most of the proposed research and conducted preliminary experiments for each of the current specific aims which support the feasibility of this grant proposal. The proposed experiments will generate novel information on the effects of hypercapnia on the alveolar epithelium and shed light on the mechanisms leading to alveolar epithelial dysfuntion which is of significance to the understanding and treatment of patients with acute lung injury.

描述（由申请人提供）：在采用“允许性高碳酸血症”策略通气的呼吸衰竭患者中观察到高 pCO2 水平。我们和其他研究人员最近报告说，pCO2 水平升高会对肺泡上皮产生有害影响。具体来说，我们报道高碳酸血症通过抑制肺泡上皮 Na,K-ATP 酶并损害肺泡液清除率，导致肺泡上皮的短期和长期功能障碍。因此，本申请的重点是确定在高碳酸血症条件下导致肺泡 Na,K-ATP 酶下调和肺泡液清除受损的具体机制/信号通路。我们建议通过四个相互关联的目标来研究高碳酸血症对肺泡上皮的影响：在与特定目标＃1相关的实验中，我们将确定可溶性腺苷酸环化酶是否参与高碳酸血症诱导的肺泡上皮中Na，K-ATP酶下调；在与特定目标#2相关的实验中，我们将确定高碳酸血症诱导的 JNK 激活是否会导致仅 LIM 结构域的蛋白 7 (LMO7) 磷酸化和 Na,K-ATP 酶内吞作用；在与特定目标#3相关的研究中，我们将确定Na,K-ATP酶泛素化是否导致其下调，并建议鉴定特定的E2和E3泛素连接酶；在与具体目标#4相关的研究中，我们将确定高碳酸血症是否会进一步损害轻度呼吸机所致肺损伤（VILI）模型中的损伤，以及sAC、JNK、LMO7和泛素化途径的下调是否会逆转高碳酸血症对啮齿类动物肺泡液清除率的有害影响。在本资助的第一个周期中，我们已经完成了大部分拟议的研究，并针对当前的每个具体目标进行了初步实验，支持了本资助提案的可行性。所提出的实验将产生有关高碳酸血症对肺泡上皮影响的新信息，并揭示导致肺泡上皮功能障碍的机制，这对于了解和治疗急性肺损伤患者具有重要意义。