Epithelium-specific deletion of TGF-β receptor type II protects mice from bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibroproliferative pulmonary disorder for which there are currently no treatments Although the etiology of IPF is unknown, dysregulated TGF-beta signaling has been implicated in its pathogenesis Recent studies also suggest a central role for abnormal epithelial repair In this study, we sought to elucidate the function of epithelial TGF-beta signaling via TGF-beta receptor II (T beta RII) and its contribution to fibrosis by generating mice in which T beta RII was specifically inactivated in mouse lung epithelium These mice, which are referred to herein as T beta RIINkx2 (1-cre) mice, were used to determine the impact of T beta RII inactivation on (a) embryonic lung morphogenesis in vivo, and (b) the epithelial cell response to TGF-beta signaling in vitro and in a bleomycin-induced, TGF-beta-mediated mouse model of pulmonary fibrosis Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, T beta RIINkx2 (1cre) mice developed emphysema, suggesting a requirement for epithelial T beta RII in alveolar homeostasis Absence of T beta RII increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic TGF-beta However, T beta RIINkx2 (1-cre) mice exhibited increased survival and resistance to bleomycin-induced pulmonary fibrosis To our knowledge, these findings are the first to demonstrate a specific role for TGF-beta signaling in the lung epithelium in the pathogenesis of pulmonary fibrosis