Alveolar Determinants: MMPs and Emphysema

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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.