Matrilysin (MMP-7) catalytic activity regulates ß-catenin localization and signaling activation in lung epithelial cells.

Matrix metalloproteinase-7 (matrilysin, MMP-7) expression is increased in epithelium by bacterial infection, inflammation, fibrosis, and in a myriad of carcinomas. It functions to degrade extracellular matrix and other pericellular substrates including the adherens junction protein E-cadherin to promote wound healing and tissue remodeling. ß-catenin functions as both a structural component of adherens junctions and as an intracellular signaling molecule. To assess if matrilysin-mediated disassembly of adherens junctions regulates ß-catenin function, we assessed effects of matrilysin catalytic activity on ß-catenin localization and signaling activity in A549 cells and in bleomycin-induced lung injury in mice. We determined that matrilysin activity releases ß-catenin from the cell membrane after which it is degraded in the cytosol. However, in the presence of a ß-catenin stabilizing Wnt signal, ß-catenin accumulated in the cytosol and activated a ß-catenin luciferase promoter. Furthermore, ß-catenin nuclear translocation and activation was impaired in matrilysin-null mice when compared to wild-type mice after bleomycin-induced lung injury. These results show identify matrilysin as a regulator of ß-catenin function in injured lung epithelium and may link extracellular proteolytic activity to cell junction disassembly and intracellular signaling.

Pulmonary macrophage subpopulations in the induction and resolution of acute lung injury.

Macrophages are key orchestrators of the inflammatory and repair responses in the lung, and the diversity of their function is indicated by their polarized states and distinct subpopulations and localization in the lung. Here, we characterized the pulmonary macrophage populations in the interstitial and alveolar compartments during the induction and resolution of acute lung injury induced by Pseudomonas aeruginosa infection. We identified macrophage subpopulations and polarity according to FACS analysis of cell surface protein markers, combined with cell sorting for gene expression using real-time PCR. With these techniques, we validated a novel, alternatively activated (M2) marker (transferrin receptor), and we described three interstitial and alveolar macrophage subpopulations in the lung whose distribution and functional state evolved from the induction to resolution phases of lung injury. Together, these findings indicate the presence and evolution of distinct macrophage subsets in the lung that serve specific niches in regulating the inflammatory response and its resolution. Alterations in the balance and function of these subpopulations could lead to nonresolving acute lung injury.