Optimizing vascular protective effects of antitrypsin in COPD

描述(由申请人提供)： 摘要：肺气肿和慢性支气管炎是慢性阻塞性肺疾病的综合征，现已超过中风成为美国第三大死因，也是退伍军人中的一种高度流行的疾病。α1抗胰蛋白酶(A1AT)是肝脏释放的一种丰富的蛋白质，具有向外全身的作用。A1AT对中性粒细胞弹性蛋白酶抑制作用的发现，提示肺基质蛋白降解是肺气肿的主要发病机制，促进了A1AT治疗肺气肿的研究。虽然A1AT替代疗法被证明对特定的A1AT缺乏症患者有效，但对于香烟烟雾(CS)诱导的肺气肿的治疗效果却令人失望。我们建议通过优化A1AT的血管保护作用来提高其治疗肺气肿的潜力。我们的建议追求新的假设，即A1AT除了具有典型的抗弹性蛋白酶丝氨酸功能外，还通过对抗细胞因子诱导的内皮激活而具有血管保护功能，但炎性细胞因子和CS降解并降低内皮细胞中A1AT的丰度。由于内皮血管细胞是对抗炎症的第一道屏障，优化A1AT在内皮细胞内的滞留和功能可能会减少炎症，并可能阻止肺气肿的进展。这项应用剖析了影响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的血管保护作用的方法(Aim 2)。我们依靠一种综合的方法，包括以肺部炎症和内皮细胞凋亡为特征的肺气肿模型，肺微循环中A1AT细胞内命运的活细胞和动物成像，以及在短期和长期接触CS期间增加A1AT血管滞留的分子和药理学方法。我们的建议虽然侧重于COPD，但对蛇针生物学和以炎症为特征的全身和肺血管疾病的病理生物学具有更广泛的影响。

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.