The Role and Regulation of TIMP-1 in Lung Inflammation

描述(申请人提供)：特发性肺纤维化(IPF)是一种以持续性炎症反应为特征的致命性肺部疾病 致伤。炎症细胞在受损肺中的积聚是 部分地通过矩阵之间的动态交互来实现 金属蛋白酶及其抑制物。组织抑制因子的表达 肺组织中金属蛋白酶-1(TIMP-1)的表达显著升高 患有炎症性肺部疾病。TIMP-1分泌增加可能有助于 调节肺损伤的炎症反应。在本提案中，我们将使用 已建立的博莱霉素肺损伤模型检测其作用及 TIMP-1在肺损伤后中性粒细胞反应中的调节作用我们的 研究表明，TIMP-1的表达显著和持久地增加 博莱霉素损伤中的炎性白细胞和肺间充质细胞 阿龙。使用TIMP-1零突变小鼠，我们发现TIMP-1缺乏引发 中性粒细胞在受损肺中聚集增加。我们正在进行的工作 提示细胞表面分子CD4O在培养肺组织中的活化 成纤维细胞选择性地诱导TIMP-1的产生 转录后调控。目的1是研究TIMP-1的作用 在中性粒细胞从血管向肺泡室的迁移中 肺部受伤。利用小鼠嵌合体治疗TIMP-1缺乏症的研究 无论是造血细胞还是肺结构细胞，都能确定 炎性和结构细胞来源的TIMP-1对中性粒细胞的调控作用 移民。同时具有TIMP-1缺陷和野生型的嵌合小鼠 将构建中性粒细胞来评估中性粒细胞来源的作用 TIMP-1在体内调节中性粒细胞迁移中的作用。建议进行研究以 博莱霉素炎性反应基因的表达谱比较 DNA微阵列技术损伤TIMP-1缺陷型和野生型肺。目标 二是研究CD4O介导的TIMP-1和MMPs的分子机制 在肺成纤维细胞中表达。有人建议进行研究来定义CD4O是否会诱导 通过使用替代的5‘转录起始点翻译TIMP-1， 提高文字记录转移率或提高翻译效率。

DESCRIPTION (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF) is a lethal pulmonary disorder characterized by persistent inflammation in response to injury. The accumulation of inflammatory cells in the injured lung is accomplished, in part, through a dynamic interaction between matrix metalloproteinases (MMP) and their inhibitors. Expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) is markedly elevated in the lungs of patients with inflammatory lung diseases. Increased secretion of TIMP-1 may function to regulate the inflammatory response to lung injury. In this proposal we will use the well established bleomycin lung injury model to examine the role and regulation of TIMP-1 in the neutrophilic response of the injured lung. Our studies demonstrate a marked and durable increase in TIMP-1 expression by inflammatory leukocytes and lung mesenchymal cells in the bleomycin injured lung. Using TIMP-1 null mutation mice, we find that TIMP-1 deficiency provokes enhanced neutrophil accumulation in the injured lungs. Our work in progress indicates that activation of the cell surface molecule CD4O on cultured lung fibroblasts selectively induces TIMP-1 production that is post-transcriptionally regulated. Aim 1 is to characterize the role of TIMP-1 in neutrophil emigration from the vascular to the alveolar compartments of the injured lung. Studies are designed using mice chimeric for TIMP-1 deficiency in either hematopoietic or lung structural cells to define the contribution of inflammatory and structural cell-derived TIMP-1 to governing neutrophil emigration. Chimeric mice that possess both TIMP-1 deficient and wild type neutrophils will be constructed to evaluate the role of neutrophil-derived TIMP-1 in modulating neutrophil emigration in vivo. Studies are proposed to compare the expression profiles of inflammatory response genes of bleomycin injured TIMP-1 deficient and wild type lungs by DNA microarray strategies. Aim 2 is to characterize the molecular mechanisms of CD4O mediated TIMP-1 and MMP expression in lung fibroblasts. Studies are proposed to define if CD4O induces TIMP-1 translation by usage of alternative 5' transcription start sites, increased transcript translocation or increased translational efficiency.