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

ABSTRACT: 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-? 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-? signaling via TGF-? receptor II (T?RII) and its contribution to fibrosis by generating mice in which T?RII was specifically inactivated in mouse lung epithelium. These mice, which are referred to herein as T?RIINkx2.1-cre mice, were used to determine the impact of T?RII inactivation on (a) embryonic lung morphogenesis in vivo; and (b) the epithelial cell response to TGF-? signaling in vitro and in a bleomycin-induced, TGF-?-mediated mouse model of pulmonary fibrosis. Although postnatally viable with no discernible abnormalities in lung morphogenesis and epithelial cell differentiation, T?RIINkx2.1-cre mice developed emphysema, suggesting a requirement for epithelial T?RII in alveolar homeostasis. Absence of T?RII increased phosphorylation of Smad2 and decreased, but did not entirely block, phosphorylation of Smad3 in response to endogenous/physiologic TGF-?. However, T?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-? signaling in the lung epithelium in the pathogenesis of pulmonary fibrosis.

SUBMITTER: Li M 

PROVIDER: S-EPMC3007138 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature