Fibrotic scarring of the lung causes significant disability, often leading to death. Persistent fibroblast proliferation is resistant to treatment and portends a poor prognosis. The expression of Thy-1 glycoprotein seems to be a key element affecting the fibrotic potential of fibroblasts. Fibroblasts lacking Thy-1 (Thy-1-) share many of the phenotypic features characteristic of fibroblasts from fibrotic lesions and have enhanced proliferative responses to fibrogenic growth factors, which may lead to their accumulation or persistence in fibrotic lesions. The proposed studies are based on the hypothesis that the expression of Thy-1 alters activation of intracellular signaling pathways and cellular responses to fibrogenic mediators, thus modulating the fibroproliferative potential of fibroblasts. The mechanisms for differential signaling and the implications for fibrosis will be explored through the following specific aims: 1) To elucidate the molecular mechanisms for the enhanced proliferative responses observed in Thy-1- fibroblasts, by defining intracellular signaling pathways modulating proliferative responses and by defining the effects of Thy-1 expression on signaling and proliferation; 2) To characterize the consequences of Thy-1 expression in experimentally-induced lung fibrosis, by comparing fibrosis in Thy-1-/- gene-targeted mice to those in wild-type mice, and in chimeric Thy-1-/- mice in which hematopoietic cell expression of Thy-1 has been restored by bone marrow transplantation; and 3) To determine the role of fibroblast Thy-1 expression in idiopathic pulmonary fibrosis, by exploring fibroblast proliferation and signaling in situ and ex vivo in explanted lungs from IPF patients undergoing lung transplantation, compared to those in control tissues. Understanding the roles of subpopulations of fibroblasts in lung fibrogenesis, and the mechanisms of their activation, is likely to provide rationale for novel cell- and pathway-specific therapeutic interventions for this debilitating process.
