Regulation of Fibroblast Phenotype in Lung Fibrosis

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DESCRIPTION (provided by applicant): Fibroblasts mediate the abnormal tissue repair characteristic of fibrosis, but their origin in fibrotic lung remains unclear. Evidence exists for alteration of existing fibroblasts, influx of fibroblast precursors, and transdifferentiation of other cell types. Many of the fibrogenic characteristics of lung fibroblasts are regulated by expression of Thy-1, an outer membrane leaflet surface protein which modulates cell adhesion and migration via signaling alterations in lipid raft domains. Loss of Thy-1 expression is associated with oncogenic transformation and anchorage-independent growth. Our laboratory has established that absence of Thy-1 correlates with enhanced proliferative responses of lung fibroblasts to fibrogenic growth factors and altered cytokine signaling, whereas presence of Thy-1 inhibits the ability of lung fibroblasts to i) activate latent transforming growth factor-beta (TGF-(), a key fibrogenic mediator; and to ii) express alpha-smooth muscle actin. Thy-1 -/- mice develop more severe fibrotic remodeling of the lung, and fibroblasts in fibroblastic foci of idiopathic pulmonary fibrosis (IPF) are predominantly Thy-1 (-). Inflammatory signaling causes shedding of Thy-1, activation of latent TGF-(, and transformation of fibroblasts into myofibroblasts. These findings support the hypothesis that loss of fibroblast Thy-1 expression is associated with a dysfunctional, profibrotic wound healing response in the lung. Preliminary data indicate that in addition to shedding, epigenetic regulation through promoter hypermethylation is an important mechanism for inhibition of Thy-1 expression. Furthermore, the majority of lung fibrocytes (bone-marrow derived cells which differentiate into myofibroblasts) are Thy-1 (-). Taken together with our previous work, these findings suggest that the regulation of Thy-1 expression, whether by shedding, transcriptional regulation, or recruitment of Thy-1 (-) cells, may present a novel therapeutic target for fibrosis. Thus the aims of the proposed studies are to: 1. define mechanisms for and consequences of Thy-1 shedding in the context of evolving fibrogenesis; 2. determine the roles of transcriptional and epigenetic regulation of Thy-1 expression in evolving fibrogenesis; and 3. define the relationship between Thy-1 expression and influx of fibrocytes and other bone marrow-derived cells into lungs undergoing fibrogenesis. Each of these aims will be addressed in a vertically-integrated approach using in vitro studies, relevant animal models and well-characterized human samples.