The Role and Regulation of TIMP-1 in Lung Inflammation

描述（由申请人提供）：特发性肺纤维化（IPF）是一种 一种致命的肺部疾病，其特征是持续的炎症反应 受伤。炎症细胞在受损肺中的积聚是 部分是通过矩阵之间的动态相互作用来实现的。 金属蛋白酶（MMP）及其抑制剂。组织抑制因子表达 金属蛋白酶-1（TIMP-1）在患者肺中显著升高， 炎症性肺病TIMP-1的分泌增加可能起作用， 调节对肺损伤的炎症反应。在本提案中，我们将使用 良好建立的博来霉素肺损伤模型来检查作用， TIMP-1在损伤肺的嗜酸性反应中的调节。我们 研究表明，TIMP-1表达的显著和持久的增加， 博莱霉素损伤肺组织中的炎性白细胞和间充质细胞 肺。使用TIMP-1无效突变小鼠，我们发现TIMP-1缺乏引起 在受伤的肺中增加了中性粒细胞的聚集。我们正在进行的工作 表明在培养的肺上细胞表面分子CD 4 O的活化 成纤维细胞选择性地诱导TIMP-1的产生， 转录后调节。目的1是表征TIMP-1在肿瘤细胞中的作用 在中性粒细胞从血管迁移到肺泡室的过程中， 受伤的肺使用TIMP-1缺陷的嵌合小鼠设计研究， 造血细胞或肺结构细胞，以确定 炎症和结构细胞源性TIMP-1对调节性中性粒细胞 移民。同时具有TIMP-1缺陷型和野生型的嵌合小鼠 将构建中性粒细胞以评价嗜中性粒细胞衍生的 TIMP-1在体内调节中性粒细胞迁移。建议开展研究， 比较博来霉素对炎症反应基因表达谱的影响 损伤的TIMP-1缺陷型和野生型肺。目的 二是探讨CD 4 O介导TIMP-1和MMP-2表达的分子机制 在肺成纤维细胞中表达。建议进行研究以确定CD 4 O是否诱导 TIMP-1翻译通过使用可选的5'转录起始位点， 增加的转录物易位或增加的翻译效率。

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.