Lung Endothelial Cell Apoptosis and Emphysema

肺内皮细胞凋亡与肺气肿

• 批准号: 8043941
• 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/8043941
• 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; 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. PUBLIC HEALTH RELEVANCE: Chronic Obstructive Pulmonary Disease (COPD) is the fourth most common diagnosis of hospitalized veterans, accounting for about 33% of all primary or secondary discharge diagnoses. Tobacco use, the most common cause of COPD, is also very common among veterans with a prevalence of 34% (compared to 22% for civilians). Thus, tobacco-induced COPD is a very costly cause of morbidity among veterans in terms of both healthcare costs and suffering. Furthermore, COPD is an important co-morbidity for other common p0roblems among veterans, such as lung cancer and atherosclerosis. Thus, it is very important to understand the mechanism of tobacco-induced lung disease. The studies proposed in this application are directly relevant to veterans' health in that these studies will determine the mechanism of injury to the lung vascular endothelium caused by tobacco and the role that this plays in development of COPD. These studies may result in development of more effective treatments for COPD.

描述(由申请人提供)： 香烟烟雾是COPD的主要原因，COPD是美国第四大死因。CS诱导的氧化应激可引起内皮细胞(EC)的凋亡，越来越多的证据表明肺泡壁细胞的凋亡在肺气肿的发生发展中起着重要作用。这项建议的总体目标是了解CS诱导的肺内皮细胞凋亡和肺气肿的机制。我们先前对小分子GTP酶的羧甲基化的研究表明，抑制RhoA GTP酶活性会导致局部黏附复合体(FAC)的破坏和肺内皮细胞的凋亡。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。目的1：我们将确定氧化剂介导的RhoA失活是否导致CSE诱导的FAC丢失和肺内皮细胞凋亡。我们以前的研究也表明，当ER分子伴侣减少时，尽管未折叠蛋白反应(UPR)被激活，EC仍会发生凋亡。我们的初步数据表明，CSE激活了UPR成分eIF2a，该成分在接触CS的小鼠肺气肿中也被激活。目的2：我们将确定UPR是否在CSE暴露时首先被激活，并在持续的氧化应激后最终在肺内皮细胞中出现缺陷。自噬是一种保护性过程，其标志物已在COPD患者的肺中得到证实。我们的初步数据显示，暴露于CSE的肺内皮细胞和暴露于CS的小鼠肺内自噬标志物的表达增加。目的3：我们将确定是否在CSE暴露时自噬被激活，并在持续的氧化应激后最终在肺内皮细胞中发生缺陷。拟议的研究将加强对肺气肿发病机制的了解，并可能导致开发这种毁灭性疾病的新治疗方法。 公共卫生相关性： 慢性阻塞性肺疾病(COPD)是住院退伍军人最常见的第四种诊断，约占所有一次或二次出院诊断的33%。吸烟是慢性阻塞性肺疾病最常见的原因，在退伍军人中也很常见，患病率为34%(相比之下，平民的患病率为22%)。因此，从医疗费用和痛苦的角度来看，烟草导致的COPD是退伍军人发病率的一个非常昂贵的原因。此外，COPD是退伍军人中其他常见问题的重要并存，如肺癌和动脉粥样硬化。因此，了解烟草所致肺部疾病的发病机制具有重要意义。本申请中建议的研究与退伍军人的健康直接相关，因为这些研究将确定烟草对肺血管内皮细胞的损伤机制，以及这种损伤在慢性阻塞性肺疾病发展中所起的作用。这些研究可能导致开发更有效的COPD治疗方法。