Indirubin alleviates bleomycin-induced pulmonary fibrosis in mice by suppressing fibroblast to myofibroblast differentiation.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial lung disease with a poor prognosis. Indirubin, a compound obtained from indigo-bearing plants or mollusks of the family Muricidae, has various bioactivities, including anti-tumor activity and anti-inflammation effect. However, whether indirubin could mediate its therapeutic effects on bleomycin (BLM)-induced pulmonary fibrosis has not been addressed. The impacts of indirubin on bleomycin (BLM)-induced pulmonary fibrosis were evaluated by pathological staining, western blot, RT-PCR and immunofluorescent staining. The effects of indirubin on fibroblast differentiation and related signaling were next investigated to demonstrate the underlying mechanisms. The results indicated that indirubin-treated mice exhibited a definitively improved survival rate than that of the BLM-induced mice in a dose-depend manner. Additionally, administration of indirubin significantly alleviated inflammatory cells infiltration in BLM mice. Importantly, indirubin provided protection for mice against BLM-induced pulmonary fibrosis as manifested by the attenuating expression of fibrotic hallmarks, including fibronectin, collagen I and α-smooth muscle actin (α-SMA). Subsequently, we providedin vitro evidence revealing that indirubin suppressed fibroblast to myofibroblast differentiation by repressed TGF-β/Smad signaling in a dose-dependent manner. Notably, our data showed that indirubin seemed to be safe in mice and fibroblasts. Overall, indirubin could protect the mice against BLM-induced pulmonary fibrosis by alleviated fibroblast differentiation and may be therapeutically beneficial for IPF patients.

Wang Q ，Yu J ，Hu Y ，Chen X ，Zhang L ，Pan T ，Miao K ，Mou Y ，Xu Y ，Xiong W ，Wang Y ... -  《-》

Curdione ameliorates bleomycin-induced pulmonary fibrosis by repressing TGF-β-induced fibroblast to myofibroblast differentiation.

Liu P ，Miao K ，Zhang L ，Mou Y ，Xu Y ，Xiong W ，Yu J ，Wang Y ... -  《RESPIRATORY RESEARCH》

Andrographolide ameliorates bleomycin-induced pulmonary fibrosis by suppressing cell proliferation and myofibroblast differentiation of fibroblasts via the TGF-β1-mediated Smad-dependent and -independent pathways.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no effective medication. Andrographolide (Andro), extracted from Chinese herbal Andrographis paniculata, could attenuate bleomycin (BLM)-induced pulmonary fibrosis via inhibition of inflammation and oxidative stress, however, the anti-fibrotic mechanisms have not been clarified. Myofibroblasts are the primary cell types responsible for the accumulation of extracellular matrix (ECM) in fibrotic diseases, and targeting fibroblast proliferation and differentiation is an important therapeutic strategy for the treatment of IPF. Hence, this study aimed to investigate the effects of Andro on the fibroblast proliferation and differentiation in the in vivo and in vitro models. The results showed that Andro improved pulmonary function and inhibited BLM-induced fibroblast proliferation and differentiation and ECM deposition in the lungs. In vitro, Andro inhibited proliferation and induced apoptosis of TGF-β1-stimulated NIH 3T3 fibroblasts and primary lung fibroblasts (PLFs). Andro also inhibited TGF-β1-induced myofibroblast differentiation and ECM deposition in both cells. We also found that Andro suppressed TGF-β1-induced Smad2/3 and Erk1/2 activation, suggesting that Smad2/3 and Erk1/2 inactivation mediates Andro-induced effects on TGF-β1-induced fibroblast proliferation and differentiation. These results indicated that Andro has novel and potent anti-fibrotic effects in lung fibroblasts via inhibition of the proliferation and myofibroblast differentiation of fibroblasts and subsequent ECM deposition, which are modulated by TGF-β1-mediated Smad-dependent and -independent pathways.

Li J ，Feng M ，Sun R ，Li Z ，Hu L ，Peng G ，Xu X ，Wang W ，Cui F ，Yue W ，He J ，Liu J ... -  《-》

Arsenic trioxide inhibits transforming growth factor-β1-induced fibroblast to myofibroblast differentiation in vitro and bleomycin induced lung fibrosis in vivo.

Luo F ，Zhuang Y ，Sides MD ，Sanchez CG ，Shan B ，White ES ，Lasky JA ... -  《RESPIRATORY RESEARCH》

Necrostatin-1 Alleviates Bleomycin-Induced Pulmonary Fibrosis and Extracellular Matrix Expression in Interstitial Pulmonary Fibrosis.

Mou F ，Mou C 《MEDICAL SCIENCE MONITOR》