The injurious effects of hypercapnia on the alveolar epithelium

高碳酸血症对肺泡上皮的损伤作用

基本信息

批准号：
8384840
负责人：
Jacob I Sznajder
金额：
$ 37.32万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/8384840
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

项目摘要

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）：使用“允许性高碳酸盐”策略通风的呼吸衰竭患者观察到高PCO2水平。我们和其他研究人员最近报告说，升高的PCO2水平可能对肺泡上皮产生有害影响。具体而言，我们报告说，高碳酸血症可通过抑制肺泡上皮Na，K-ATPase和损害肺泡液清除率，从而导致肺泡上皮的短期和长期功能障碍。因此，该应用的重点是确定导致肺泡Na，K-ATPase下调和肺泡流体清除率损伤的特定机制/信号通路。我们建议通过四个相互关联的目的研究高碳酸盐对肺泡上皮的影响：在与特定目的＃1有关的实验中，我们将确定可溶性腺苷环酶是否参与过度capnia诱导的Na，K- Atpase下属的Na，肺泡上皮上的k- atpase下调；在与特定目标＃2有关的实验中，我们将确定高碳酸血症诱导的JNK激活是否导致仅LIM域蛋白7（LMO7）磷酸化和Na，K-ATPase内吞作用；在与特定目标3有关的研究中，我们将确定Na，K-ATPase泛素化是否导致其下调，并建议识别特定的E2和E3泛素连接酶；在与特定目的4有关的研究中，我们将确定高碳酸血症是否会进一步损害轻度呼吸机诱导的肺损伤模型（VILI）的损伤，以及SAC，JNK，LMO7和泛素化途径的下调是否会逆转超核对杆验流体对杆的有害影响的有害影响。在这笔赠款的第一个周期中，我们已经完成了大多数提议的研究，并针对当前每个特定目的进行了初步实验，以支持该赠款提案的可行性。所提出的实验将生成有关高碳酸脂蛋白对肺泡上皮的影响的新颖信息，并阐明导致肺泡上皮功能障碍的机制，这对急性肺损伤患者的理解和治疗至关重要。