An Investigation into Classical and Novel Roles of Vimentin Intermediate Filaments in the Lung

Vimentin is a type III intermediate filament (IF) protein normally expressed in cells of mesenchymal origin, such as macrophages, lymphocytes, and fibroblasts. Classically, vimentin IFs were regarded as static structures maintaining cellular shape and mechanical integrity. This view is rapidly expanding to include previously unappreciated regulatory and signaling functions in injury and disease. The purpose of this project was to determine the role of vimentin in lung pathophysiology, using both in vitro and in vivo models of lung injury.;The first part of this project investigated the effects of vimentin expression on wound repair in an in vitro model of lung injury. We demonstrate that alveolar epithelial cells, which normally do not express vimentin protein, upregulate vimentin in a TGF-beta1-dependent manner, leading to increased cellular migration and rates of wound repair. These effects were prevented by pharmacologic inhibition of the Smad/TGF-beta1 pathway and by adenoviral-mediated knockdown of vimentin expression. Conversely, over-expression of vimentin protein was sufficient to increase rates of wound closure to the same extent as TGF-beta1 treatment. These results demonstrate that vimentin is required and sufficient for increased rates of cell migration and wound repair in an in vitro model of lung injury.;The role of vimentin in pathophysiology was further elucidated by using a clinically-relevant murine model of lung injury and fibrosis. We demonstrate that vimentin-deficient mice are protected from inflammation and fibrosis in the lung. Vimentin was required for the maturation of interleukin (IL)-1beta and downstream release of pro-inflammatory (e.g., IL-6) and pro-fibrotic (e.g., TGF-beta1) cytokines through a previously unknown interaction with the NLRP3 inflammasome. These results suggest that vimentin acts as signaling platform required for the innate immune response. Together, the results of this project demonstrate classical and novel roles for vimentin in alveolar epithelial cell migration and inflammatory cell signaling with important implications for treatment of lung injury and disease.