Mutual promotion of mitochondrial fi ssion and oxidative stress contributes to mitochondrial-DNAmediated infl ammation and epithelial-mesenchymal transition in paraquat-induced pulmonary fibrosis  

作　　者：Jie Zhang Wen-jing Li Shi-qiang Chen Ze Chen Chen Zhang Ran Ying Hong-bing Liu Long-wang Chen Ya-hui Tang Zhong-qiu Lu Guang-ju Zhao 

机构地区：[1]Department of Emergency Medicine,the First Affi liated Hospital of Wenzhou Medical University,Wenzhou 325000,China [2]Wenzhou Key Laboratory of Emergency and Disaster Medicine,Wenzhou 325000,China

出　　处：《World Journal of Emergency Medicine》2023年第3期209-216,共8页世界急诊医学杂志（英文）

基　　金：supported by the Wenzhou Municipal Science and Technology Bureau(Y2020092);partly by the Key Specialty of Traditional Chinese Medicine of Zhejiang Province in the 13th Five-Year Plan period(Emergency Department).

摘　　要：BACKGROUND:Pulmonary fibrosis(PF)is one of the main causes of death in patients with paraquat(PQ)poisoning.This study aimed to evaluate the relationship between mitochondrial fi ssion and oxidative stress in PQ-induced epithelial-mesenchymal transition(EMT)and PF.METHODS:C57BL/6 mice and MLE-12 cells were exposed to PQ to construct a PF model in vivo and in vitro.Histological changes in the lungs were examined by hematoxylin and eosin(H&E)staining.Mitochondrial morphology was detected by MitoTracker®Deep Red FM or transmission electron microscopy(TEM).Western blotting and immunofluorescence were used to determine the expression of protein.The migration ability of the cells was detected by the cell scratch test.Mitochondrial DNA(mtDNA)levels were assessed by real-time polymerase chain reaction(PCR).Enzyme-linked immunosorbent assay(ELISA)was applied to detect cytokine levels.Superoxide dismutase(SOD)activity and the levels of glutathione(GSH)and malondialdehyde(MDA)were detected by chemichromatometry.RESULTS:PQ exposure caused EMT and PF in vivo and in vitro.PQ destroyed mitochondrial structure and enhanced the expression of dynamin-related protein 1(Drp1),which were accompanied by oxidative stress.Inhibiting mitochondrial fission using mitochondrial division inhibitor-1(Mdivi-1),a selective inhibitor of Drp1,attenuated PQ-induced EMT and oxidative damage.Treatment with N-acetyl-L-cysteine(NAC),an antioxidant,reduced Drp1 expression,attenuated mitochondrial structure damage and inhibited PQ-induced EMT and PF.Both Mdivi-1 and NAC treatment markedly suppressed mtDNA release,the expression of Toll-like receptor 9(TLR9)and phosphorylation(P)-NF-κB p65 as well as cytokines(interleukin 6[IL-6],interleukin-1β[IL-1β],and tumor necrosis factor-α[TNF-α])production.CONCLUSION:Mutual promotion of mitochondrial fission and oxidative stress contributes to EMT in PQ-induced PF,which is associated with the mtDNA/TLR9/NF-κB pathway.

关 键 词：PARAQUAT Mitochondrial fi ssion Oxidative stress Epithelial-mesenchymal transition Mitochondrial DNA 

分 类 号：R595.4[医药卫生—内科学]