We have observed the strong expression of the MMP matrilysin by alveolar epithelial cells following alveolar injury associated with organizing diffuse alveolar damage, post-bone marrow transplant idiopathic pneumonia syndrome, and interstitial pneumonitis. Matrilysin is not found in the respiratory epithelium of normal lung. Following lung surgery, matrilysin was detected by immunohistochemistry and in situ hybridization in """"""""row"""""""" of type II cells marching across denuded alveolar walls. Matrilysin-positive cells were found largely in areas of damaged or destroyed basement membrane and rested on a fibronectin-containing matrix. Matrilysin is frequently an """"""""epithelial cell-derived"""""""" MMP, but other MMPs which are known to be produced by some epithelial cells, namely collagenase-I, stromelysin-1, and gelatinase B (MMP-9), were not produced by human lung respiratory epithelium. In vitro studies of both rat and human alveolar epithelial cells demonstrated strong capacity for matrilysin mRNA and protein expression. Expression of matrilysin was also markedly induced in airway epithelial cells in cystic fibrosis and severe asthma, again suggesting a function in injury-mediated responses. Supporting this concept, we found enhanced matrilysin expression by migrating human airway (tracheal) epithelial cells in an ex vivo model of tissue repair. In such explants, following mechanical wounding, immunoreactive matrilysin was present both within and underneath the migrating tracheal epithelial cells. Based upon these observations, we hypothesize that matrilysin expression by type II pneumocytes accompanies severe alveolar injury, and speculate that the proteolytic activity of this MMP is needed to facilitate cell migration and repair. To address this hypothesis, we propose the following specific aims: 1) we will examine the effect of matrilysin expression by alveolar epithelial cells on alveolar repair following experimental acute lung injury; 2) we will determine the effects of matrilysin on human and rodent alveolar epithelial cell behavior in vitro; and 3) we will define how matrilysin expression is regulated in human and rodent alveolar epithelial cells. To accomplish these objectives, we will employ diverse cell biological and molecular biologic approaches including the study of matrilysin-deficient versus wild-type mice. We will determine whether matrilysin is necessary for the migration of type II pneumocytes, whether contact of cells with provisional matrix proteins stimulates matrilysin expression, and the intracellular mechanisms of matrilysin induction in alveolar epithelial cells.
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