Lung Endothelial Cell Apoptosis and Emphysema

肺内皮细胞凋亡与肺气肿

• 批准号: 8391601
• 负责人: Sharon Irene Smith Rounds
• 金额: --
• 依托单位: PROVIDENCE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391601
• 关键词: 3T3 Cells; Accounting; Acute; Alveolar; Alveolar Cell; Alveolar wall; Anoikis; Antioxidants; Apoptosis; Atherosclerosis; Attenuated; Autophagocytosis; Autophagolysosome; Autophagosome; Blood Vessels; Blood capillaries; Butyric Acids; Cause of Death; Cells; Chronic; Chronic Obstructive Airway Disease; Cigarette Smoker; Cigarette smoke-induced emphysema; Comorbidity; Complex; Data; Defect; Development; Diagnosis; Disease; Endoplasmic Reticulum; Endothelial Cells; Epithelial Cells; F-Actin; Failure; Fiber; Focal Adhesion Kinase 1; Focal Adhesions; Guanosine Triphosphate Phosphohydrolases; Health; Health Care Costs; Injury; Lung; Lung diseases; Lysosomes; Malignant Epithelial Cell; Malignant neoplasm of lung; Mediating; Molecular Chaperones; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Mus; Oxidants; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Play; Predisposition; Prevalence; Process; Proteins; Pulmonary Emphysema; Reporting; Resistance; Risk Factors; Role; Signal Transduction; Smoker; Stomach Carcinoma; Testing; Tobacco; Tobacco use; Vascular Endothelium; Veterans; capillary; cigarette smoke-induced; cigarette smoking; effective therapy; endoplasmic reticulum stress; knock-down; novel therapeutic intervention; oxidant stress; prevent; pro-apoptotic protein; public health relevance; response; rho GTP-Binding Proteins

DESCRIPTION (provided by applicant): Cigarette smoke (CS) is the primary cause of COPD, the fourth leading cause of death in the US. CS-induced oxidant stress causes endothelial cell (EC) apoptosis, and there is growing evidence that apoptosis of alveolar wall cells plays a role in the development of emphysema. The overall objective of this proposal is to understand mechanisms of CS-induced lung EC apoptosis and emphysema. Our previous studies on carboxylmethylation of small GTPases indicated that inhibition of RhoA GTPase activity causes focal adhesion complex (FAC) disruption and lung EC apoptosis. We present preliminary data indicating that CS extract (CSE) disrupts FAC via oxidative stress, causes EC apoptosis, and decreases RhoA activity. Aim 1: We will determine if oxidant- mediated RhoA inactivation causes CSE-induced loss of FAC and apoptosis of pulmonary EC. Our previous studies also demonstrated that EC apoptosis occurs despite activation of the unfolded protein response (UPR) when ER molecular chaperones are decreased. Our preliminary data indicate that CSE activates a UPR component, eIF2a, which was also activated in emphysematous lungs of mice exposed to CS. Aim 2: We will determine if UPR is first activated upon CSE exposure and ultimately defective after prolonged oxidative stress in pulmonary EC. Autophagy is a protective process, markers of which have been demonstrated in lungs of COPD patients. Our preliminary data demonstrate increased expression of autophagy markers in lung endothelial cells exposed to CSE and in lungs of mice exposed to CS. Aim 3: We will determine if autophagy is activated upon CSE exposure and ultimately defective after prolonged oxidative stress in pulmonary EC. The proposed studies will enhance understanding of the pathogenesis of emphysema and may result in develop of new therapeutic approaches to this devastating disease.

描述（由申请人提供）： 香烟烟雾（CS）是慢性阻塞性肺病（COPD）的主要原因，慢性阻塞性肺病是美国第四大死因。 CS 诱导的氧化应激导致内皮细胞 (EC) 凋亡，越来越多的证据表明肺泡壁细胞凋亡在肺气肿的发生中发挥作用。该提案的总体目标是了解 CS 诱导的肺 EC 细胞凋亡和肺气肿的机制。我们之前对小 GTP 酶羧甲基化的研究表明，抑制 RhoA GTP 酶活性会导致粘着斑复合物 (FAC) 破坏和肺 EC 凋亡。我们提供的初步数据表明 CS 提取物 (CSE) 通过氧化应激破坏 FAC，导致 EC 凋亡并降低 RhoA 活性。目标 1：我们将确定氧化剂介导的 RhoA 失活是否会导致 CSE 诱导的 FAC 丢失和肺 EC 凋亡。我们之前的研究还表明，当 ER 分子伴侣减少时，尽管未折叠蛋白反应 (UPR) 被激活，但 EC 细胞凋亡仍会发生。我们的初步数据表明，CSE 激活 UPR 成分 eIF2a，该成分在暴露于 CS 的小鼠的肺气肿肺中也被激活。目标 2：我们将确定 UPR 是否在 CSE 暴露后首先被激活，并在肺 EC 中长期氧化应激后最终出现缺陷。自噬是一种保护性过程，其标志物已在慢性阻塞性肺病患者的肺部得到证实。我们的初步数据表明，暴露于 CSE 的肺内皮细胞和暴露于 CS 的小鼠肺中自噬标记物的表达增加。目标 3：我们将确定自噬是否在 CSE 暴露后被激活，并在肺 EC 中长期氧化应激后最终出现缺陷。拟议的研究将增进对肺气肿发病机制的了解，并可能导致开发针对这种破坏性疾病的新治疗方法。