Nagilactone D ameliorates experimental pulmonary fibrosis in vitro and in vivo via modulating TGF-beta/Smad signaling pathway

摘要

Pulmonary fibrosis is a prototypic chronic progressive lung disease with high morbidity and mortality worldwide. Novel effective therapeutic agents are urgently needed owing to the limited treatment options in clinic. Herein, nagilactone D (NLD), a natural dinorditerpenoid obtained from Podocarpus nagi, was found to suppress transforming growth factor-beta 1 (TGF-beta 1)-mediated fibrotic process in vitro and bleomycin (BLM)-induced pulmonary fibrosis in vivo. NLD attenuated TGF-beta 1-induced expression of fibrotic markers including type I and III collagen, fibronectin, alpha-SMA, and CTGF in human pulmonary fibroblasts (WI-38 VA-13 and HLF-1 cells). Mechanism study indicated that NLD suppressed TGF-beta 1-induced up-regulation of T beta R I, and Smad2 phosphorylation, nuclear translocation, and transcriptional activation. Moreover, NLD ameliorated BLM-induced histopathological abnormalities in the lungs of experimental fibrotic mice, suppressed synthesis of relative fibrotic markers and fibroblast-to-myofibroblast transition, as well as BLM-induced up-regulation of TOR I expression and Smad signaling in mouse lungs. These data collectively support NLD to be a potential therapeutic agent for pulmonary fibrosis.