Tanshinone IIA Alleviates Pulmonary Fibrosis by Inhibiting Pyroptosis of Alveolar Epithelial Cells Through the MAPK Signaling Pathway.

Abstract

The current dearth of safe and efficacious pharmaceutical interventions for pulmonary fibrosis (PF) has prompted investigations into alternative treatments. This study aim to investigate the underlying mechanisms of Tanshinone IIA in the treatment of PF. PF was induced in a mouse model by intratracheal infusion of bleomycin (BLM), followed by gavage administration of varying concentrations of Tanshinone IIA. Lung tissue was obtained for pathological slides, proteomic and transcriptomic analyses. The target was predicted and analyzed using network pharmacology. Initially, an in vitro model in A549 cells was established by adding BLM, followed by treatment with varying concentrations of Tanshinone IIA. Subsequently, NAC and the ERK inhibitor, U0126, were individually introduced. Treatment with Tanshinone IIA in vivo decreased lung tissue lesions. Proteomic, transcriptomic, and network pharmacology analyses suggested that Tanshinone IIA may offer therapeutic benefits for PF by mitigating oxidative stress damage via the MAPK signaling pathway. In vitro studies demonstrated that BLM treatment in A549 cells induced exposure of the N-terminal end of the pyroptosis core protein GSDMD, and elevated oxidative stress levels in A549 cells, concomitant with the upregulation of P-ERK protein expression. Subsequent administration of Tanshinone IIA, NAC, and U0126 reduced the number of A549 cells undergoing pyroptosis, decreased oxidative stress levels, and decreased P-ERK protein expression. These findings suggested that Tanshinone IIA potentially delays the progression of PF. The mechanism of action involves the inhibition of oxidative stress and reduced epithelial cell pyroptosis via the MAPK-related pathway. The findings may provide a new reference for treatment of PF.