Peimine Alleviated Bleomycin-Induced Pulmonary Fibrosis in Mice Through Reducing Epithelial-Mesenchymal Transition, Inflammation and Oxidative Stress and Regulating Host Metabolism

Abstract

Peimine (PM), derived from Fritillaria thunbergii Miq, has been demonstrated with protective effects on pulmonary fibrosis (PF). However, the detailed mechanisms of PM on PF remain unknown. The aim of current study was to assess the therapeutic effects and the possible mechanism of PM on PF. In this study, mice received bleomycin (BLM) injection to induce PF and then received the treatment of PM orally. The therapeutic effects of PM on PF were firstly assessed through histopathological staining (hematoxylin and eosin and Masson staining) and measuring hydroxyproline (HYP) level in lung. Then, we measured the levels of epithelial-mesenchymal transition (EMT)-related markers (vimentin and E-cadherin), pro-inflammatory factors (interleukin [IL]-1β, IL-6, and tumor necrosis factor alpha [TNF-α]), and oxidative stress-related indicators (superoxide dismutase[SOD], malondialdehyde [MDA] and glutathione peroxidase [GSH-Px]) in lung. Furthermore, untargeted metabolomics were employed to explore the effects of PM on metabolites in lung. PM treatment improved the pathological changes including reducing the infiltration of inflammatory cells and decreasing collagen deposition, and decreasing the HYP level in lung in PF mice. Moreover, PM treatment up-regulated E-cadherin and down-regulated vimentin, decreased IL-1β, IL-6 and TNF-α expression, increased SOD and GSH-Px activities, and decreased MDA level in lung. Untargeted metabolomics analysis showed that PM altered the metabolites in lung of mice with BLM-induced PF. The differential metabolites were mainly associated with tryptophan metabolism, nicotinate and nicotinamide metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, and D-glutamine and D-glutamate metabolism. PM exhibited therapeutic effects on BLM-induced PF mice including reducing collagen deposition, inhibiting EMT and reducing inflammation and oxidative stress. The mechanism of PM on PF may be associated with regulating tryptophan metabolism, nicotinate and nicotinamide metabolism, alanine, aspartate and glutamate metabolism, arginine biosynthesis, and D-glutamine and D-glutamate metabolism in lung.