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Initial CDAS Request Approval
Jul 13, 2005
MT1-MMP and EMMPRIN in Cigarette Smoke-Induced Lung Inflammation and Emphysema
Proteases, principally from inflammatory cells, are pivotal in the pathogenesis of cigarette smoke-induced emphysema. Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a cell-surface MMP that cleaves fibrillar collagens, many matrix substrates and other substrates, including a1-antitrypsin. We have found MT1-MMP expression in lung tissue exhibiting emphysema, and rapid up-regulation of MT1-MMP in alveolar macrophages of mice exposed to cigarette smoke. We hypothesize that MT1-MMP has a central role in the pathogenesis of cigarette smoke-induced alveolar inflammation and destruction via effects on migration of inflammatory cells and degradation of lung extracellular matrix. To test this hypothesis we will evaluate monocytes and alveolar macrophages from smokers and former smokers with and without emphysema for expression of MT1-MMP and for MT1-MMP-dependent migration to chemokines. The monocytes for these studies will be obtained from subjects recruited from the local population of NLST participants using their CT scan to identify long-term smokers with or without emphysema. The effect of MT1-MMP on cell migration will also be assessed using macrophages from mice with a targeted deletion of MT1-MMP. Lung tissue from patients having transplants for emphysema or lung surgery for other conditions will be examined by immunohistochemistry and in situ hybridization for MT1-MMP in relation to emphysema pathology. The regulation of lung matrix metalloproteinases (MMPs) in cigarette smoke-induced inflammation and emphysema is not well understood. We have found that extracellular matrix metalloproteinase inducer (EMMPRIN), a transmembrane molecule that stimulates the expression of MT1-MMP and other MMPs, is increased in smokers lungs, and in lung macrophages and epithelial cells of mice exposed to cigarette smoke. We hypothesize that EMMPRIN is involved in the over-expression of MT1-MMP and other MMPs in the lungs of smokers. To test this hypothesis we will evaluate monocytes and alveolar macrophages from smokers with and without emphysema for expression of EMMPRIN. These subjects will be recruited from the local population of NLST participants using their CT scan to identify long-term smokers with or without emphysema. Lung tissue from patients having transplants for emphysema or lung surgery for other conditions will be examined by immunohistochemistry and in situ hybridization for EMMPRIN in relation to emphysema pathology. To test directly the role of EMMPRIN in emphysema pathogenesis we will subject EMMPRIN deficient mice to cigarette smoke using a protocol that reproducibly causes emphysema within six months.
Aim 1: Determine the role of the MT1-MMP in cigarette smoke-induced lung inflammation We will determine the relationship between MT1-MMP production by monocytes in response to cigarette smoke and the development of emphysema in cigarette smokers who are participating in the NLST. We will determine the difference in migration of monocytes and alveolar macrophages isolated from former smokers with and without emphysema (as determined by quantitative analysis of their lung density by chest CT) in the presence of an MT1-MMP functional blocking antibody. We will examine the emigration of inflammatory cells in vivo into the lungs of mice with and without functional alleles for MT1-MMP after cigarette smoke exposure. Aim 2: Determine the role of MT1-MMP in cigarette smoke-induced emphysema We will determine MT1-MMP activity in heterogeneous areas of emphysematous lungs and correlate activity with local emphysema severity. We will use laser capture microdissection (LCM) to retrieve alveolar macrophages from heterogeneous sites in emphysematous lungs and correlate MT1-MMP expression with the local emphysema severity. We will quantify air space enlargement after chronic cigarette smoke exposure in mice with and without functional alleles for the main inhibitor of MT1-MMP (TIMP-2) and MMP-2, an elastase activated by MT1-MMP. Aim 3: Determine the role of EMMPRIN in cigarette smoke-induced emphysema We will compare EMMPRIN expression by freshly isolated peripheral blood monocytes from smokers with and without emphysema who are participating in the NLST. As in Aim 1 we will determine if there is emphysema by quantitative analysis of lung density by chest CT. .As in Aim 2, we will perform LCM on heterogeneous areas of lung tissue from other subjects with emphysema who are undergoing lung surgery to retrieve alveolar macrophage and bronchial epithelial cell mRNA to correlate expression of EMMPRIN with local emphysema severity and MMP synthesis. We will determine the role of EMMPRIN in the pulmonary inflammation and emphysema induced by cigarette smoke by comparing wild-type and EMMPRIN deficient mice exposed to cigarette smoke.
The role of matrix metalloproteinase-9 in cigarette smoke-induced emphysema.
Atkinson JJ, Lutey BA, Suzuki Y, Toennies HM, Kelley DG, Kobayashi DK, Ijem WG, Deslee G, Moore CH, Jacobs ME, Conradi SH, Gierada DS, Pierce RA, Betsuyaku T, Senior RM
Am. J. Respir. Crit. Care Med.
2011 Apr; Volume 183 (Issue 7): Pages 876-84