Mechanism Of Nintedanib In Improving Pulmonary Fibrosis By Modulating PI3K/Akt/mTOR Pathway In Mice

Objective:Idiopathic Pulmonary Fibrosis(IPF)seriously threathens human life and health,and no curative therapy is available at present.Nintedanib is the first agent approved by the US Food and Drug Administration(FDA)in order to treat IPF;however,its mechanism of inhibition of IPF is still elusive.According to recent studies,nintedanib is a potent inhibitor.It can antagonize platelet-derived growth factor(PDGF),basic fibroblast growth factor(b-FGF),vascular endothelial growth factor(VEGF),etc.,to inhibit pulmonary fibrosis.Whether there are other signaling pathways involved in IPF remains unknown.This study focused on investigating the therapeutic efficacy of nintedanib in bleomycin-mediated pulmonary fibrosis(PF)mice through PI3K/Akt/m TOR pathway.Methods:After bleomycin(BLM)induced pulmonary fibrosis model in mice,the mice were randomly divided into five groups:(1)normal control group,(2)BLM model control group,(3)low-dose Nidanib administration model group,(4)medium-dose Nidanib administration model group,(5)high-dose Nidanib administration model group.For lung tissues,morphological changes were found by HE staining and Masson staining,ELISA method was used to detect inflammatory factors,alkaline water method to estimate collagen content,and western blotting for protein levels.TUNEL staining and immunofluorescence methods were used to analyze the effect of nintedanib on lung tissue and the impacts and underlying mechanisms of bleomycin-induced pulmonary fibrosis.Results:After 28 days,bleomycin-treated mice developed significant pulmonary fibrosis.Relative to bleomycin-treated mice,nintedanib-treated mice had markedly reduced degrees of PF.In addition,nintedanib showed lung-protective effects by up-regulating antioxidant levels,down-regulating inflammatory protein expression,and reducing collagen accumulation.We demonstrated that nintedanib ameliorated bleomycin-induced lung injury by inhibiting the P13K/Akt/m TOR pathway as well as apoptosis.In addition,significant improvement in pulmonary fibrosis was seen after nintedanib(30/60/120 mg/kg body weight/day)treatment through a dose-dependent way.Histopathological results further corroborated the effect of nintedanib treatment on remarkably attenuating bleomycin-mediated mouse lung injury.Conclusions:According to our findings,nintedanib restores the antioxidant system,suppresses pro-inflammatory factors,and inhibits apoptosis.Nintedanib can alleviate bleomycin induced inflammation,oxidative stress,and apoptosis by downregulating the PI3K/Akt/m TOR pathway,ultimately improving pulmonary fibrosis.