Alveolar Determinants: MMPs and Emphysema

肺泡决定因素：MMP 和肺气肿

• 批准号: 7231247
• 负责人: ROBERT M SENIOR
• 金额: $ 47.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231247
• 关键词: Air; Alleles; Alveolar; Alveolar Macrophages; Alveolar wall; Animals; Area; Blocking Antibodies; Bronchoalveolar Lavage; Cell surface; Cells; Chemotactic Factors; Chest; Chronic; Chronic Obstructive Airway Disease; Cigarette Smoker; Cigarette smoke-induced emphysema; Cleaved cell; Complement; Data; Development; Elastin; Emigrations; Endopeptidases; Epithelial Cells; Exhibits; Extracellular Matrix; Fibrillar Collagen; Gelatinase A; Gene Deletion; Glucocorticoids; Harvest; Human; Immigration; In Vitro; Inflammation; Inflammatory; Lung; Lung Inflammation; Matrix Metalloproteinases; Measures; Messenger RNA; Mus; Particulate; Pathogenesis; Peptide Hydrolases; Pneumonia; Polymerase Chain Reaction; Principal Investigator; Production; Protease Inhibitor; Protein C Inhibitor; Protein Overexpression; Pulmonary Emphysema; Recruitment Activity; Regulation; Resistance; Resources; Role; Severities; Site; Smoker; Smoking; Structure of parenchyma of lung; Tissues; Tobacco smoke; Up-Regulation; X-Ray Computed Tomography; cigarette smoke-induced; cigarette smoking; human MMP14 protein; in vivo; inhibitor/antagonist; knockout gene; laser capture microdissection; lung imaging; macrophage; migration; monocyte; peripheral blood; programs; research study; response; tissue processing

The protease-antiprotease hypothesis of emphysema pathogenesis has support from many human and animal studies. A longstanding tenet of this hypothesis has been that proteases relevant to emphysema pathogenesis must be capable of degrading elastin. However, data in recent years indicates that collagenolytic activity may induce emphysema. Membrane-type 1 matrix metalloproteinase (MT1-MMP), a cell-surface MMP that cleaves fibrillar collagens, and EMMPRIN, an inducer of MT1-MMP, are detectable in emphysematous lung tissue, suggesting a role for MT1-MMP in emphysema pathogenesis. Moreover, monocyte migration in vitro requires MT1-MMP so that MT1- MMP is likely to be involved in the accumulation of macrophages in the lungs from smoking as well as in destruction of alveolar walls. The studies we propose will determine the roles of MT1-MMP and EMMPRIN in the pathogenesis of emphysema. We will determine whether levels of MT1-MMP and EMMPRIN expression by monocytes, at baseline and upon stimulation, have a relationship to monocyte migration among smokers with and without emphysema, and whether levels of MT1-MMP and EMMPRIN expression by alveolar macrophages correlate with emphysema as determined by chest computed tomography (CT). To accomplish these objectives we will assess the role of MT1-MMP on the migration of smokers' monocytes with MT1-MMP blocking antibodies, and we will measure MT1- MMP and EMMPRIN mRNAs by quantitative PCR on alveolar macrophages harvested by bronchoalveolar lavage and laser capture microdissection. These studies will be complemented by analyses of the pulmonary responses to tobacco smoke in mice with targeted deletions ("knockouts") of the genes for MT1-MMP or EMMPRIN, and in mice with deletion of the gene for TIMP-2, the principal inhibitor of MT1-MMP. Taken together, the proposed studies will contribute new understanding of mechanisms of pulmonary inflammation and emphysema that occur in response to tobacco smoke.

肺气肿发病机制的蛋白酶-抗蛋白酶假说得到了许多人的支持， 和动物研究。这一假说的一个长期原则是， 肺气肿的发病机制必须能够降解弹性蛋白。然而，近年来的数据 表明胶原溶解活性可诱导肺气肿。1型膜基质 金属蛋白酶（MT 1-MMP），一种切割纤维状胶原的细胞表面MMP，和EMMPRIN，一种 在肺气肿肺组织中可检测到MT 1-MMP诱导剂，提示MT 1-MMP在肺气肿中的作用。 肺气肿发病机制。此外，单核细胞在体外迁移需要MT 1-MMP，因此MT 1-MMP在体外迁移时是必需的。 MMP可能参与吸烟引起的肺巨噬细胞的积累， 破坏肺泡壁。我们提出的研究将确定MT 1-MMP的作用， EMMPRIN在肺气肿发病机制中的作用我们将确定MT 1-MMP和 在基线和刺激后，单核细胞的EMMPRIN表达与 吸烟者肺气肿和非肺气肿患者的单核细胞迁移，以及MT 1-MMP 肺泡巨噬细胞表达EMMPRIN与肺气肿相关 计算机断层扫描（CT）。为了实现这些目标，我们将评估MT 1-MMP在 吸烟者单核细胞的迁移与MT 1-MMP阻断抗体，我们将测量MT 1-MMP-1， 通过定量PCR检测肺泡巨噬细胞MMP和EMMPRIN mRNA， 支气管肺泡灌洗和激光捕获显微切割。这些研究将得到以下方面的补充： 在具有靶向缺失（“敲除”）的小鼠中对烟草烟雾的肺反应的分析 MT 1-MMP或EMMPRIN的基因，而在TIMP-2基因缺失的小鼠中， MT 1-MMP抑制剂。总之，拟议的研究将有助于对 吸烟引起的肺部炎症和肺气肿的机制。