Smoke Induced Airway Injury in the Lung

描述(申请人提供)：香烟烟雾是慢性阻塞性肺疾病和肺癌的主要原因，研究表明，香烟烟雾可以直接诱导肺实质中基质金属蛋白酶(MMP)的表达。因此，COPD的研究重点在于提高我们对烟雾在肺内引起的特定细胞和生化损伤的了解，这是至关重要的。已经证明，当MMPs在转基因小鼠的肺中表达时，会导致肺气肿的发生，从而证明了MMPs在肺破坏中的关键作用。此外，我们的实验室还发现，人胶原酶MMP1在COPD患者的上皮细胞中表达增加，并确定了吸烟诱导MMP1表达的分子调控。此外，我们在MMP1启动子的香烟烟雾反应元件中发现了几个新的多态。阻断MMPs是否会保护肺部免受香烟烟雾的破坏和疾病，仍有待确定。此外，MMP1中这种新定义的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，我们将验证我们将通过遗传学和药理学方法确定抑制胶原酶是否可以防止肺气肿发展的假设。我们在实验室里有可以完成这项研究的动物模型和化合物。在第二个目标中，我们将利用烟雾暴露的小鼠和兔模型来确定阻断香烟烟雾诱导途径是否能保护肺部炎症和肺气肿。初步研究已经确定了针对这一途径的候选小分子。最后，我们将与Edwin Silverman博士和Michael Cho博士合作，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中的SNP或吸烟诱导途径中的基因是否会增加肺气肿的易感性。完成这项建议后，我们的目标是确定胶原酶是否是肺气肿的治疗靶点，以及这一途径是否可用作疾病易感性标记。好了！

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. !