Preotease/Cathepsin-Mediated Apoptosis in COPD

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）包括肺气肿和慢性支气管炎。这是一个迫切的临床问题，也是一个深刻的未满足的医疗需求。关于肺气肿的发病机制已经提出了许多理论。“蛋白酶/抗蛋白酶”假说认为，正常肺受到“抗蛋白酶屏障”的保护，肺气肿是由蛋白酶的增加和/或抗蛋白酶的减少引起的。据推测，慢性阻塞性肺病的Th1炎症是导致这些改变的原因。最近，结构性细胞凋亡在肺气肿中被证实。Th1诱导蛋白酶/抗蛋白酶改变的机制尚不清楚。重要的是，在肺或其他器官中，Th1反应诱导组织损伤和破坏的机制也尚未确定。我们的研究表明，香烟烟雾（CS）通过IFN-y依赖的机制诱导肺气肿，IFN-y通过新的组织蛋白酶介导的上皮细胞凋亡/DNA损伤（CMEA）途径引起肺气肿。他们还证明CMEA参与了一个增加炎症和蛋白酶负担的正反馈循环。我们推测：(1)IFN-y在肺气肿的发病机制中起关键作用。(2) IFN-y通过早期生长反应基因1 （Egr-1）和外在和内在凋亡途径诱导的一种新的CMEA反应诱导肺气肿。(3) CMEA在调节组织炎症和蛋白酶负荷的caspase-11和caspase-1依赖性扩增环中起核心作用。我们将验证这一假设，并探讨th1诱导组织破坏的机制，目的如下。目的1：表征IFN-y系统的改变，以及这些改变在CS和IFN-y诱导的肺气肿发病机制中的作用。目的2：表征cs暴露小鼠和IFN-y Tg小鼠组织蛋白酶系统的反应及其在肺细胞凋亡、损伤和肺气肿发病机制中的作用。目的3：明确Egr-1、外源性和内源性凋亡途径以及末端效应caspases在IFN-y和cs诱导的肺细胞凋亡、损伤和肺气肿发病机制中的作用。目的4：明确CMEA对cs暴露小鼠和IFN-y Tg小鼠炎症和蛋白酶负荷的调节作用及其机制。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) includes emphysema and chronic bronchitis. It is a pressing clinical problem and a profound unmet medical need. A number of theories of emphysema pathogenesis have been proposed. The "protease/ antiprotease" hypothesis contends that the normal lung is protected by an "antiprotease shield" and that emphysema is caused by an increase in proteases and/or a decrease in antiproteases. It has been speculated that the Th1 inflammation in COPD is responsible for these alterations. More recently, structural cell apoptosis has been documented in emphysema. The mechanism(s) of Th1 induction of protease/ antiprotease alterations is poorly understood. Importantly, the mechanism(s) by which Th1 responses induce tissue injury and destruction, in the lung or other organs, have also not been defined. Our studies demonstrate that cigarette smoke (CS) induces emphysema via an IFN-y-dependent mechanism and that IFN-y causes emphysema via a novel cathepsin-mediated epithelial cell apoptosis/DNA injury (CMEA) pathway. They also demonstrated that CMEA participates in a positive feedback loop that augments inflammation and protease burden. We hypothesize that: (1) IFN-y plays a critical role in the pathogenesis of pulmonary emphysema. (2) IFN-y induces emphysema via a novel CMEA response that is induced by early growth response gene 1 (Egr-1) and the extrinsic and intrinsic apoptosis pathways. (3) CMEA plays a central role in a caspase-11 and caspase-1-dependent amplification loop that regulates tissue inflammation and protease burden. We will test this hypothesis and address the mechanisms of-Th1-induced tissue destruction with the following aims. Aim 1: Characterize the alterations in the IFN-y system and the role(s) of these alterations in the pathogenesis of CS and IFN-y-induced emphysema. Aim 2: Characterize the cathepsin system responses in CS-exposed and IFN-y Tg mice and their role(s) in the pathogenesis of pulmonary apoptosis, injury and emphysema. Aim 3: Define the roles of Egr-1, the extrinsic and intrinsic apoptosis pathways and terminal effector caspases in the pathogenesis of IFN-y and CS-Induced pulmonary apoptosis, injury and emphysema. Aim 4: Define the contribution of and mechanism by which CMEA regulates inflammation and protease burden in CS-exposed and IFN-y Tg mice.