Sinomenine attenuates pulmonary fibrosis by downregulating TGF-β1/Smad3, PI3K/Akt and NF-κB signaling pathways

Abstract

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic progressive and irreversible interstitial lung disease. Pulmonary fibrosis (PF) has become more common among people severely infected with COVID-19, with IPF being the most common form since this virus became a global epidemic disease in 2019. At present, the etiology is unclear, the treatment methods are limited, and the prognosis is quite poor. Sinomenine (SIN) extracted from the dried stems of Sinomenium actum, is used in traditional Chinese medicine to treat several diseases, alleviate liver fibrosis injury, and improve airway remodeling caused by chronic asthma. However, the mechanism used by SIN to combat PF is unclear. Therefore, this work describes the effect of SIN on IPF. Methods PF was induced by bleomycin (BLM) in C57BL-6J mice, and then Inflammatory factors, lung histopathological changes, and TGF-β/Smad signaling pathway were evaluated. Serum-starved human embryonic lung fibroblasts (HFL-1) and A549 cells were treated with different doses of SIN. We observed the effects of SIN on HFL-1 and A549 cells, including proliferation and migration, the transformation of fibroblasts into myofibroblasts (FMT), epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition and signal pathways (TGF-β/Smad, PI3K/Akt and NF-κB signal pathways). In addition, the TGF-β receptor inhibitor SB-431542 was used to evaluate not only the classical Smad pathways downstream of TGF-β, but also non-Smad pathways (PI3K/Akt and NF-κB signaling pathways) involved in the process of PF. Results The in vivo experiments showed that SIN reduced the pathological changes in the lung tissue induced by BLM, reduced the abnormal expression of inflammatory cytokines, and improved the weight and survival rate of mice induced by BLM. The in vitro experiments showed that SIN inhibited the migration and proliferation of HFL-1 and A549 cells by inhibiting TGF-β1/Smad3, PI3K/Akt, and NF-κB pathways, prevented the FMT of HFL-1, reversed the EMT of A549 cells, restored the balance of matrix metalloenzymes, and reduced the expression of ECM proteins. Conclusion SIN attenuated PF by down-regulating TGF-β/Smad3, PI3K/Akt, and NF-κB signaling pathways, being a potential effective drug in the treatment of PF.