Berberine inhibits Smad and non-Smad signaling cascades and enhances autophagy against pulmonary fibrosis

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2015-09, Vol.93 (9), p.1015-1031
• Main Authors: Chitra, Palanivel, Saiprasad, Gowrikumar, Manikandan, Ramar, Sudhandiran, Ganapasam
• Format: Article
• Language: English
• Subjects: Animals; Autophagy - drug effects; Berberine - therapeutic use; Biomedical and Life Sciences; Biomedicine; Bleomycin - toxicity; Human Genetics; Immunoblotting; Immunohistochemistry; Internal Medicine; Male; Microscopy, Confocal; Molecular Medicine; Original Article; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - drug therapy; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - drug effects; Smad Proteins - metabolism
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-015-1283-1

Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative lung disorder of unknown aetiology. Transforming growth factor-β1 (TGF-β1)-mediated Smad and non-Smad signaling cascades are considered as central players in accelerating pulmonary fibrosis. We earlier reported berberine’s amelioration against TGF-β1-mediated pro-fibrotic effects in bleomycin-induced pulmonary fibrosis. The present study aimed to determine the regulatory role of berberine on abrogated Smad 2/3 and FAK-dependent PI3K/Akt-mTOR signaling cascades in bleomycin-induced pulmonary fibrosis. Male Wistar rats were subjected to single intratracheal instillation of bleomycin (2.5 U/kg) on day 0, and berberine treatments were provided in either preventive or therapeutic modes, respectively. Berberine mitigated the elevated expression of fibrotic markers, α-smooth muscle actin (α-SMA), fibronectin, collagens I and III and reversed bleomycin-induced ultrastructural alterations in the lungs. Berberine inhibited the bleomycin-induced raise in p-Smad 2/3 and enhanced Smad 7 expression. Berberine blocked the activation of FAK and PI3K/Akt against bleomycin-induced dysregulation, with subsequent raise in PTEN expression. In addition, by inhibiting p-mTOR, berberine stimulated autophagy as evidenced by increase in Beclin-1, LC3-II levels with enhanced autophagosome formation. Cumulatively, through targeted inhibition of dysregulated Smad and FAK-dependent PI3K/Akt-mTOR signaling axis, berberine attenuated the fibrotic insults of bleomycin. Key message Berberine inhibits Smad 2/3 activation and enhances Smad 7 in bleomycin-induced rat lungs. Bleomycin-induced activation of FAK is inhibited by berberine. Berberine inhibits bleomycin-induced activation of PI3K/Akt cascade. Berberine inhibits mTOR activation to enhance autophagy and suppresses fibrotic markers.