Alveolar Determinants: MMPs and Emphysema

关于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信条是，与 肺气肿的发病机制必须能够降解弹性蛋白。然而，近年来的数据显示， 提示胶原酶活性可诱发肺气肿。膜型1基质 金属蛋白酶(MT1-MMPs)，一种分解纤维状胶原蛋白的细胞表面MMPs，以及EMMPRIN，一种 在肺气肿肺组织中可检测到MT1-基质金属蛋白酶的诱导物，提示MT1-基质金属蛋白酶在肺气肿肺组织中的作用。 肺气肿发病机制。此外，单核细胞在体外的迁移需要MT1-MMPs，从而使MT1-MMP. 基质金属蛋白酶可能参与吸烟引起的巨噬细胞在肺内的积聚。 对肺泡壁的破坏。我们提出的研究将确定MT1-基质金属蛋白酶和 EMMPRIN在肺气肿发病机制中的作用我们将测定MT1-MMPs和 单核细胞在基线和刺激时EMMPRIN的表达与以下因素有关 伴和不伴肺气肿的吸烟者之间的单核细胞迁移，以及MT1-基质金属蛋白酶水平 肺泡巨噬细胞EMMPRIN表达与肺气肿的关系 计算机断层扫描(CT)。为了实现这些目标，我们将评估MT1-MMPs在 吸烟者单核细胞与MT1-基质金属蛋白酶阻断抗体的迁移，我们将检测MT1- 定量聚合酶链式反应检测肺泡巨噬细胞中基质金属蛋白酶和肌动蛋白表达 支气管肺泡灌洗和激光捕获显微解剖。这些研究将得到以下补充 烟草烟雾靶向缺失(“基因敲除”)小鼠的肺部反应分析 MT1-MMP或EMMPRIN的基因，以及TIMP-2基因缺失的小鼠，主要 MT1-基质金属蛋白酶的抑制物。综上所述，拟议的研究将有助于对 烟草烟雾引起的肺部炎症和肺气肿的机制。

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.