Smoke Induced Airway Injury in the Lung

描述（申请人提供）：吸烟是慢性阻塞性肺病和肺癌的主要原因，研究表明吸烟可直接诱导肺实质中基质金属蛋白酶（MMP）的表达。因此，COPD研究的重点是提高我们对肺内烟雾引起的特定细胞和生化损伤的理解。已经证明，MMPs在转基因小鼠的肺中表达时，会导致肺气肿的发展，因此记录了MMPs在肺破坏中的关键作用。此外，我们的实验室已经发现慢性阻塞性肺病患者上皮细胞中MMP1（一种人类胶原酶）的表达增加，并确定了烟雾诱导MMP1表达的分子调控。此外，我们在MMP1启动子的香烟烟雾响应元件中发现了几个新的多态性。阻断MMPs是否会保护肺部免受香烟烟雾引起的破坏和疾病仍有待确定。此外，这一新定义的MMP1中香烟烟雾反应元件在疾病易感性中的作用尚不清楚。因此，我们建议进行以下研究。首先，我们将测试假设，我们将通过遗传和药理学方法确定是否抑制胶原溶解酶保护肺气肿的发展。我们在实验室里有动物模型和化合物来完成这项研究。在第二个目标中，我们将利用烟雾暴露的小鼠和兔子模型确定香烟烟雾诱导通路的阻断是否可以保护肺部炎症和肺气肿。初步研究已经确定了靶向这一途径的候选小分子。最后，在与Edwin Silverman博士和Michael Cho的合作下，我们将利用COPD基因研究的样本来翻译我们的发现。在这里，我们将确定MMP1、MMP13或烟雾诱导通路内的基因中的snp是否与肺气肿易感性有关。在完成这项提议后，我们的目标是确定胶原溶解酶是否是肺气肿的治疗靶点，以及该途径是否可作为疾病易感性标志物。

DESCRIPTION (provided by applicant): Cigarette smoke is the major cause of COPD and lung cancer and studies have demonstrated that cigarette smoke can directly induce matrix metalloproteinase (MMP) expression in the lung parenchyma. Thus, it is essential that COPD research focuses on improving our understanding of the specific cellular and biochemical injury induced by smoke within the lung. It has been demonstrated that MMPs when expressed in the lung of transgenic mice, lead to the development of emphysema therefore documenting the critical role for MMPs in lung destruction. Also, our laboratory has identified increased expression of MMP1, a human collagenase, in the epithelial cell of patients with COPD and defined the molecular regulation of the smoke induced expression of MMP1. Also, we identified several novel polymorphisms within this cigarette smoke responsive element of the MMP1 promoter. It remains to be determined whether blockade of MMPs will protect the lung from destruction and disease initiated by cigarette smoke. Furthermore, the role of this newly defined cigarette smoke responsive element in MMP1 in disease susceptibility is not know. Therefore, we propose to perform the following studies. First, we will test the hypothesis we will determine through genetic and pharmacological methodology whether inhibition of the collagenolytic enzymes protects from the development of emphysema. We have within the laboratory the animal models and compounds available to complete this study. In the second aim we will identify whether blockade of the cigarette smoke induction pathway protects from lung inflammation and emphysema utilizing the mouse and rabbit model of smoke exposure. Preliminary studies have already identified candidate small molecules targeting this pathway. Finally, in collaboration with Dr. Edwin Silverman and Michael Cho we will translate our findings utilizing samples from the COPD gene Study. Here we will determine whether SNPs within MMP1, MMP13 or genes within the smoke induced pathway confer susceptibility to emphysema. Upon completion of this proposal our goal is to determine whether the collagenolytic enzymes are a therapeutic target in emphysema and whether this pathway is useful as a disease susceptibility marker.