Resolution of acute lung injury (ALI) requires coordinated and effective tissue repair and remodeling to reestablish a functional epithelial barrier. In particular, restoration of the normal air space architecture requires reconstitution of denuded alveolar epithelial type I cells that undergo apoptotic and necrotic death following ALI. Regeneration of alveolar epithelial type II cells is important in reestablishing surfactant production and ion transport and importantly suppresses fibroblast proliferation and matrix deposition after ALI. However, resolution of ALI can result in disordered repair of the alveolus, characterized by fibrocellular proliferation. The cellular regulatory mechanisms necessary for coordinating functional repopulation and reconstitution of the alveolar epithelial barrier remain unclear. Transdifferentiation of epithelial cells into matrix producing fibroblasts with enhanced matrix turnover has been suggested as one mechanism by which disordered epithelial remodeling promotes progression to fibroproliferation in ALI. This mesenchymal transdifferentiation has been characterized in part by expansion of vimentin IF positive cells, which are derived from alveolar epithelial cells following ALI. Vimentin is a type III intermediate filament protein normally expressed in cells of mesenchymal origin. However, vimentin expression has been described in epithelial cells involved in pathological or physiological processes which require epithelial cell migration. Accumulating evidence supports the model in which epithelial cell acquisition of migratory properties is associated with the loss of epithelial characteristics and the gain of mesenchymal properties. This proposal will focus on the role of keratin and vimentin intermediate filaments during wound repair and remodeling following ALI. We have formulated three interrelated specific aims to study the regulation of keratin and vimentin intermediate filaments in an in vivo and in vitro model of ALI:
Specific aim#1. To determine whether keratin and/or vimentin IPs are required for normal alveolar epithelial repair and remodeling in an in vivo and in vitro model of lung injury.
Specific Aim #2. To determine whether TGF-p1/Smad and/or (J-catenin/TCF transcriptionally regulate keratin and vimentin genes in alveolar epithelial cells to increase the rate of AEC migration and promote wound healing.
Specific aim #3. To determine whether the degradation of keratin and vimentin intermediate filaments is mediated by the ubiquitin-proteasome pathway in alveolar epithelial cells during wound repair and remodeling.
The experiments proposed for these aims will integrate studies examining the cellular and molecular mechanisms regulating the induced expression, re-organization and/or disassembly of intermediate filaments and the resultant alveolar epithelial cell transdifferentiation associated with ALI. Completion of the proposed studies will provide novel insights on the role of keratin and vimentin IFs in the pathogenesis of alveolar epithelial transdifferentiation and dysfunction, which is of biological and physiological importance in patients with ALI.
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