The Role and Regulation of TIMP-1 in Lung Inflammation

TIMP-1在肺部炎症中的作用和调节

• 批准号: 6621887
• 负责人: DAVID K MADTES
• 金额: $ 34.6万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6621887
• 关键词: CD40 molecule; bleomycin; cell migration; fibroblasts; gene expression; genetic translation; idiopathic pulmonary fibrosis; immune response genes; inflammation; laboratory mouse; lung injury; metalloendopeptidases; microarray technology; neutrophil; posttranslational modifications; tissue /cell culture; tissue inhibitor of metalloproteinases

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.

描述（由申请人提供）：特发性肺纤维化（IPF）是一种致命性肺部疾病，其特征是持续性炎症反应 以致受伤。炎症细胞在受伤的肺部积聚 部分地通过矩阵之间的动态相互作用来完成 金属蛋白酶（MMP）及其抑制剂。组织抑制剂的表达 患者肺部金属蛋白酶-1 (TIMP-1) 显着升高 患有炎症性肺部疾病。 TIMP-1 分泌增加可能起到以下作用： 调节对肺损伤的炎症反应。在这个提案中我们将使用 建立良好的博来霉素肺损伤模型来检查其作用和 TIMP-1 在受损肺中性粒细胞反应中的调节。我们的 研究表明 TIMP-1 表达显着且持久的增加 博莱霉素损伤的炎性白细胞和肺间质细胞 肺。使用 TIMP-1 无效突变小鼠，我们发现 TIMP-1 缺陷会引发 受伤肺部的中性粒细胞积聚增强。我们的工作正在进行中 表明培养肺细胞表面分子 CD4O 的激活 成纤维细胞选择性诱导 TIMP-1 的产生 转录后调控。目标 1 是描述 TIMP-1 的作用 中性粒细胞从血管迁移至肺泡区 肺部受伤。研究设计使用 TIMP-1 缺陷嵌合小鼠 造血细胞或肺结构细胞来定义 炎症和结构细胞衍生的 TIMP-1 控制中性粒细胞 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。建议研究 比较博莱霉素炎症反应基因的表达谱 通过 DNA 微阵列策略损伤 TIMP-1 缺陷型和野生型肺。目的 图2是表征CD4O介导的TIMP-1和MMP的分子机制 在肺成纤维细胞中表达。建议进行研究以确定 CD4O 是否会诱导 通过使用替代的 5' 转录起始位点进行 TIMP-1 翻译， 增加转录本易位或提高翻译效率。