Smoke Induced Airway Injury in COPD

描述（由申请人提供）：COPD是一种高度流行的疾病，是大多数国家残疾和死亡的重要原因。在美国，估计有超过1400万人患有这种疾病。COPD的主要病因是吸烟。最近的研究表明，肺上皮细胞是这种疾病的发病机制的积极参与者，并在肺对香烟烟雾的反应中起着关键作用。我们的实验室已经发现MMP-1在肺气肿患者的肺上皮细胞中表达，而在正常对照中不表达。此外，在肺中表达MMP-1的转基因动物随着时间的推移发生进行性肺破坏，肺顺应性增加，与肺气肿一致。通过体外和体内研究，我们已经证明，烟雾暴露直接激活肺上皮内的MAP激酶通路，从而诱导可能参与COPD发病机制的基因的表达。通过这些研究，我们已经表明，烟雾可以直接诱导上皮细胞内MMP-1的表达。这是通过激活MAP激酶途径发生的。在本申请中，我们建议进一步研究肺上皮、胶原酶和诱导胶原酶表达的信号级联在COPD中的作用。我们还通过与Peter帕雷博士及其团队合作，探索COPD的遗传学，扩大了我自己实验室的专业知识。我们假设，在COPD中，烟雾诱导的损伤和持续性肺破坏的一个原因是通过激活肺上皮内的MAP激酶途径诱导MMP表达。我们将在三个具体目标中检验这一假设：（1）描述MMP-1启动子内的香烟烟雾反应元件;（2）确定MMP-1启动子多态性与COPD易感性和COPD严重程度之间的关联;（3）检验香烟烟雾激活MAP激酶是导致组织破坏和肺气肿形成的基因激活中的关键事件这一假设。COPD研究的重点是提高我们对吸烟引起的肺内特定细胞和生化损伤的理解。这些研究将有助于深入了解烟雾和MAP激酶信号在COPD气道损伤中的作用。研究吸烟后蛋白酶表达的转录调控因子将为COPD的发病机制提供新的思路。

DESCRIPTION (provided by applicant): COPD is highly prevalent disease, and is an important cause of disability and death in most countries. In the United States, it is estimated that over 14 million people suffer from this disease. The major etiological agent in COPD is cigarette smoke. Recent studies indicate that the lung epithelium is an active participant in the pathogenesis of this disease and plays a critical role in the lung response to cigarette smoke. Our laboratory has found that MMP-1 is expressed in epithelial cells of the lung from patients with emphysema and not in normal controls. In addition, transgenic animals that express MMP-1 in their lung develop progressive lung destruction over time with an increase in lung compliance consistent with emphysema. Through in vitro and in vivo studies, we have demonstrated that smoke exposure directly activates the MAP kinase pathway within the lung epithelium thus inducing expression of genes potentially involved in the pathogenesis of COPD. Through these studies, we have shown that smoke can directly induce MMP-1 expression within epithelial cells. This occurs through the activation of the MAP kinase pathway. In this application, we propose to further examine the role of the lung epithelium, collagenases, and the signaling cascade that induces collagenase expression in COPD. We are also expanding the expertise of my own laboratory by collaborations with Dr. Peter Pare and his group to explore genetics of COPD. We hypothesize that in COPD, one cause of smoke induced injury and persistent lung destruction is the induction of MMP expression by the activation of the MAP Kinase pathway within the epithelium of the lung. We will test this hypothesis in three specific aims: (1) Characterize the cigarette smoke responsive elements within the MMP-1 promoter; (2) Determine associations between polymorphisms in the MMP-1 promoter and susceptibility with COPD and COPD severity; and (3) Test the hypothesis that MAP kinase activation by cigarette smoke is a critical event in the activation of genes leading to tissue destruction and emphysema formation. It is essential that COPD research focus on improving our understanding of the specific cellular and biochemical injury induced by smoke within the lung. The proposed studies will provide insight into the role of smoke and MAP kinase signaling in airway injury, which occurs in COPD. The identification of transcription factors regulating protease expression in post smoke exposure will provide novel insight into the pathogenesis of COPD.