Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial lung disease without any effective treatment. Berberine (BBR), a botanical alkaloid, possesses extensive biological activities and has significant therapeutic value in various diseases. However, the effect and potential mechanisms of BBR on pulmonary fibrosis remain elusive. In vivo, BBR was administered by gavage following intratracheal instillation of bleomycin (BLM) in a mouse model from Day 1 to Day 20. In vitro, Human Lung Fibroblast (HLF) and A549 cell lines were used to explore the effects of BBR on transforming growth factor β1 (TGF-β1) treated cells. Both cell lines were transfected with a lentivirus carrying TGF-β receptor 2 (TGFBR2) knockdown genes, and the autophagy inhibitor chloroquine (CQ) and PI3K inhibitor LY294002 were employed to investigate the underlying effects of BBR on TGF-β signaling and autophagy in pulmonary fibrosis. BBR administration attenuates pulmonary inflammation and fibrosis of BLM-induced mice in vivo. Analogously, BBR treatment significantly alleviates matrix collagen deposition and reduces the expression of fibrotic markers in TGF-β1-treated human lung fibroblasts (HLF) and alveolar epithelial cell (A549) in vitro. Mechanistically, we found that BBR downregulates the expression of TGFBR2 and suppresses TGF-β/Smad2/3 signaling in vivo and in vitro. Furthermore, BBR inhibits the activation of the PI3K/AKT/mTOR pathway and autophagy, then downregulates the expression of pro-fibrotic genes. The effect of BBR on pulmonary fibrosis was further verified using both TGF-β1-treated HLF and A549 cells with the addition of the inhibitors of PI3K, LY294002, and autophagy, CQ in vitro, respectively. Our study suggests that BBR can inhibit pulmonary fibrosis by down-regulating the expression of TGFBR2, attenuating TGF-β/Smad2/3 signal, and activating autophagy through phosphorylation of PI3K/AKT/mTOR.
Zhao et al. (Sun,) studied this question.