Tetramethylpyrazine prevents liver fibrotic injury in mice by targeting hepatocyte-derived and mitochondrial DNA-enriched extracellular vesicles  

作　　者：Ya-jing Li Run-ping Liu Ming-ning Ding Qi Zheng Jian-zhi Wu Xiao-yong Xue Yi-qing Gu Bo-ning Ma Ya-jie Cai Shuo Li Sheng Lin Lu-yong Zhang Xiaojiaoyang Li 

机构地区：[1]School of Life Sciences,Beijing University of Chinese Medicine,Beijing,100029,China [2]School of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing,100029,China [3]Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing,Dongzhimen Hospital,Beijing University of Chinese Medicine,Beijing,100029,China [4]Center for Drug Screening and Pharmacodynamics Evaluation,School of Pharmacy,Guangdong Pharmaceutical University,Guangzhou,510006,China

出　　处：《Acta Pharmacologica Sinica》2022年第8期2026-2041,共16页中国药理学报（英文版）

基　　金：supported by the Beijing Municipal Science&Technology Commission(Grant No.7212174 to XL);National Natural Science Foundation of China(Grant No.82004045 to XL);Beijing Nova Program of Science&Technology(Grant No.Z191100001119088 to XL,Grant No.Z201100006820025 to RL);the Young Talents Promotion Project of China Association of Traditional Chinese Medicine(Grant No.2020-QNRC2-01 to XL);Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.ZYYCXTD-C-202006 to XL).

摘　　要：Liver fibrosis is the common consequence of almost all liver diseases and has become an urgent clinical problem without efficient therapies.Recent evidence has shown that hepatocytes-derived extracellular vesicles(EVs)play important roles in liver pathophysiology,but little is known about the role of damaged hepatocytes-derived EVs in hepatic stellate cell(HSC)activation and following fibrosis.Tetramethylpyrazine(TMP)from Ligusticum wallichii Franchat exhibits a broad spectrum of biological activities including liver protection.In this study,we investigated whether TMP exerted liver-protective action through regulating EV-dependent intercellular communication between hepatocytes and HSCs.Chronic liver injury was induced in mice by CCl_(4)(1.6 mg/kg,i.g.)twice a week for 8 weeks.In the last 4 weeks of CCl_(4) administration,mice were given TMP(40,80,160 mg·kg^(-1)·d^(-1),i.g.).Acute liver injury was induced in mice by injection of a single dose of CCl_(4)(0.8 mg/kg,i.p.).After injection,mice were treated with TMP(80 mg/kg)every 24 h.We showed that TMP treatment dramatically ameliorated CCl_(4)-induced oxidative stress and hepatic inflammation as well as acute or chronic liver fibrosis.In cultured mouse primary hepatocytes(MPHs),treatment with CCl_(4) or acetaminophen resulted in mitochondrial dysfunction,release of mitochondrial DNA(mtDNA)from injured hepatocytes to adjacent hepatocytes and HSCs through EVs,mediating hepatocyte damage and fibrogenic responses in activated HSCs;pretreatment of MPHs with TMP(25μM)prevented all these pathological effects.Transplanted serum EVs from TMP-treated mice prevented both initiation and progression of liver fibrosis caused by CCl_(4).Taken together,this study unravels the complex mechanisms underlying the protective effects of TMP against mtDNA-containing EV-mediated hepatocyte injury and HSC activation during liver injury,and provides critical evidence inspiring the development of TMP-based innovative therapeutic agents for the treatment of liver fibrosis.

关 键 词：liver fibrosis TETRAMETHYLPYRAZINE CCL4 ACETAMINOPHEN extracellular vesicle intercellular communication mouse primary hepatocytes hepatic stellate cells 

分 类 号：R285.5[医药卫生—中药学]