Preotease/Cathepsin-Mediated Apoptosis in COPD

描述(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。这是一个紧迫的临床问题，也是一个严重的未得到满足的医疗需求。关于肺气肿的发病机制，已经提出了许多学说。“蛋白水解酶/抗蛋白水解酶”假说认为，正常肺受到“抗蛋白水解酶屏障”的保护，而肺气肿是由蛋白水解酶的增加和/或抗蛋白水解酶的减少引起的。据推测，慢性阻塞性肺疾病的Th1炎症是这些变化的原因。最近，在肺气肿中发现了结构性细胞凋亡。Th1诱导蛋白水解酶/抗蛋白水解酶改变的机制(S)尚不清楚。重要的是，Th1反应导致肺或其他器官组织损伤和破坏的机制(S)也尚未确定。我们的研究表明，香烟烟雾通过一种依赖于干扰素的机制诱发肺气肿，而干扰素-γ通过一种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水解酶负担的正反馈循环。我们推测：(1)干扰素-γ在肺气肿的发病机制中起重要作用。(2)干扰素-γ通过早期生长反应基因1(Egr-1)诱导的CMEA反应以及外源性和内源性细胞凋亡途径诱导肺气肿的发生。(3)CMEA在caspase-11和caspase-1依赖的扩增环中发挥核心作用，该环调节组织炎症和蛋白酶负荷。我们将验证这一假说，并解决-Th1诱导组织破坏的机制，目的如下。目的1：探讨干扰素-γ系统的改变及其在CS和干扰素-γ诱导的肺气肿发病机制中的作用(S)。目的：研究暴露于CS和干扰素-γ的TG小鼠的组织蛋白酶系统反应及其在肺细胞凋亡、损伤和肺气肿发病机制中的作用(S)。目的：明确Egr-1、内源性和外源性细胞凋亡途径以及终末效应半胱氨酸天冬氨酸氨基转移酶在干扰素-γ和半胱氨酸诱导的肺细胞凋亡、损伤和肺气肿发病机制中的作用。目的：明确CMEA对CS暴露和干扰素-γTG小鼠炎症和蛋白水解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.