Fibroblast is believed to be the primary effector in idiopathic pulmonary fibrosis (IPF), a progressive lung disorder characterized by aberrant tissue remodeling and the formation of fibroblastic foci. Due to the complicated etiology and mechanism, there are few effective drugs for this fatal disease. Shikonin (SHI), which is the major ingredient isolated from the plant Lithospermum Erythrorhizon, has long been used as traditional medicine for many diseases including inflammation and cancer. The roles of SHI in attenuating skin scar and renal fibrosis by reducing TGFβ1-stimulated fibroblast activation are also reported. But whether SHI works on IPF which exhibits both inflammatory and carcinoma-like features remains unknown. In this study, using isolated pulmonary fibroblasts, we demonstrated that SHI inhibited the proliferation, migration of fibroblasts, enhanced cell apoptosis and led to cell cycle arrest at G1 and G2/M phase. Moreover, SHI reduced the production of α-SMA, fibronectin, collagen I and III in response to TGF-β induction in pulmonary fibroblasts, and all of these gene production is the key component of extracellular matrix for tissue remodeling for IPF. The phosphorylation of Akt was down-regulated, p53 increased, the mRNA levels of p21 and p27 enhanced after SHI treatments. The phosphorylation of both p38 MAPK and Akt stimulated by TGF-β was reduced after SHI treatments. Collectively, these data indicate that SHI has a strong cytotoxicity in pulmonary fibroblast via inhibiting Akt activation signaling pathway, and attenuates TGF-β induced extracellular matrix genes production in pulmonary fibroblasts via modulating the activities of p38 MAPK and Akt. SHI might serve as a therapeutically candidate for IPF patients.
Keywords: Akt; IPF; Proliferation; Shikonin; p38 MAPK.
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