Antifibrotic effects of cyclosporine A on TGF-β1-treated lung fibroblasts and lungs from bleomycin-treated mice: role of hypoxia-inducible factor-1α

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder that is characterized by aberrant tissue remodeling and the formation of fibroblastic foci that are composed of fibrogenic myofibroblasts. TGF-beta 1 is one of the factors that are responsible for fibrosis as it promotes fibroblast to myofibroblast differentiation (FMD) and is associated with up-regulation of a-smooth muscle actin. Therefore, inhibition of FMD may represent an effective strategy for the treatment of IPF. Here, we describe the treatment of human lung fibroblasts (WI-38 and HFL-1 cells) with cyclosporine A (CsA), which reduces TGF-beta 1-induced FMD via degradation of hypoxia-inducible factor-1 alpha (HIF-1 alpha). In addition, in primary myofibroblast-like cells that were obtained from a patient with pulmonary fibrosis, treatment with CsA and an HIF-1 alpha inhibitor (HIFi) decreased the expression levels of a-smooth muscle actin and fibronectin, which indicated that CsA and HIFi promote dedifferentiation of myofibroblasts. In mice intratracheally administered CsA or HIFi at an early fibrotic stage [ 7, 8, and 9 d postinstillation (dpi) of bleomycin], marked alleviation of lung fibrosis was observed at 14 dpi. These results suggest that CsA exhibits antifibrotic effects by degrading HIF-1 alpha and that the CsA-HIF-1 alpha axis provides new insights into therapeutic options for the treatment of IPF.