Optimizing vascular protective effects of antitrypsin in COPD

优化抗胰蛋白酶对 COPD 的血管保护作用

• 批准号: 8696830
• 负责人: Irina Petrache
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696830
• 关键词: Acute; Acute-Phase Proteins; Address; Affect; Alveolar; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptosis Inhibitor; Apoptotic; Attenuated; Biological Availability; Biology; Blood Vessels; Calpain; Cardiovascular Diseases; Caspase; Cause of Death; Cell Death; Cells; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Cigarette smoke-induced emphysema; Clathrin; Cysteine Protease; Data; Development; Disease; Effectiveness; Elastases; Endocytosis; Endothelial Cells; Endothelium; Failure; Feedback; Funding; Health; High Prevalence; Image; In Vitro; Inflammation; Inflammatory; Injury; Knowledge; Learning; Leukocyte Elastase; Life; Liver; Longevity; Lung; Lung Inflammation; Mediating; Microcirculation; Modeling; Molecular; Myocardial; Patients; Population; Process; Progress Reports; Property; Protein C Inhibitor; Proteins; Proteolysis; Pulmonary Emphysema; Quality of life; Research; Resolution; Risk; Serine Protease; Serpins; Smoking; Stroke; Structure; Syndrome; Therapeutic; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vasculitis; Veterans; Work; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; cigarette smoke-induced; cigarette smoking; cigarette smoking; cytokine; improved; in vivo; novel; novel therapeutics; outreach; overexpression; protective effect; response; uptake

DESCRIPTION (provided by applicant): ABSRACT: Emphysema and chronic bronchitis comprise the syndrome of COPD, now surpassing stroke as the 3rd leading cause of death in the US and a highly prevalent disease in Veterans. Alpha 1 antitrypsin (A1AT) is an abundant protein released by the liver, with outreaching systemic actions. The discovery of the A1AT inhibitory function against neutrophil elastase implicated the lung matrix proteolysis as a major pathogenic mechanism of emphysema and prompted the study of A1AT as therapy for emphysema patients. While proven effective for select patients with A1AT-deficiency, A1AT replacement has disappointed as treatment for cigarette smoke (CS)-induced emphysema. We propose to improve the therapeutic potential of A1AT for emphysema by optimizing its vascular protective effects. Our proposal pursues the novel hypothesis that A1AT has a vascular protective function in addition to its canonical anti- elastase serpin function, by opposing cytokine-induced endothelial activation, but that inflammatory cytokines and CS degrade and decrease the abundance of A1AT in endothelial cells. Since endothelial vascular cells are the first defense against inflammation, optimizing the retention and function of A1AT within the endothelium might decrease inflammation, and may halt emphysema progression. This application dissects the factors and mechanisms that affect the retention of A1AT in lung endothelial cells (Aim 1), and studies approaches to optimize the vascular protective effects of A1AT (Aim 2). We rely on an integrated approach involving the CS model of emphysema characterized by lung inflammation and endotehlial cell apoptosis, on live cell and animal imaging of A1AT intracellular fate in the lung microcirculation, and on molecular and pharamcoligical approaches to increase the A1AT vascular retention during short- and long- term CS exposure. Our proposal, while focusing on COPD, has broader impact with regards to serpin biology and the pathobiology of systemic and pulmonary vascular diseases characterized by inflammation.

描述（由申请人提供）： ABSRACT：肺气肿和慢性支气管炎包括COPD综合征，现在超过中风，是美国的第三大死亡原因，在退伍军人中是高度普遍的疾病。 Alpha 1抗胰蛋白酶（A1AT）是肝脏释放的丰富蛋白质，采用了伸出的系统性作用。对中性粒细胞弹性蛋白酶的A1AT抑制作用的发现，将肺基质蛋白水解作为肺气肿的主要致病机制，并促使将A1AT研究作为肺气肿患者的治疗。虽然证明对患有A1AT缺乏症的精选患者有效，但A1AT替代者对香烟烟雾（CS）诱导的肺气肿的治疗感到失望。我们建议通过优化其血管保护作用来提高A1AT对肺气肿的治疗潜力。我们的提议提出了一个新的假设，即A1AT通过反对细胞因子诱导的内皮激活，除了其规范抗弹性酶Serpin功能外具有血管保护功能，但炎症细胞因子和CS降解并减少内皮细胞中A1AT的丰度。由于内皮血管细胞是首次防御炎症的防御，因此优化内皮内A1AT的保留率和功能可能会减少炎症，并且可能会阻止肺气肿的进展。该应用剖析了影响A1AT在肺内皮细胞中保留的因素和机制（AIM 1），并研究了优化A1AT血管保护作用的研究方法（AIM 2）。我们依靠涉及肺气肿的CS模型的综合方法，其特征在于肺部炎症和内膜细胞凋亡，肺微循环中A1AT细胞内命运的活细胞和动物成像，以及在短期和长期cs cs中增加A1AT血管持续性的分子和Paramcoligical方法。我们的建议虽然专注于COPD，但对SERPIN生物学以及以炎症为特征的系统性和肺血管疾病的病理生物学具有更大的影响。