BMSC-derived exosomes ameliorate sulfur mustard-induced acute lung injury by regulating the GPRC5A-YAP axis

查看全文 作　　者：Guan-chao [1]Mao;Chu-chu [1]Gong;Zhen [1,2]Wang;Ming-xue [1]Sun;Zhi-peng [1]Pei;Wen-qi [1]Meng;Jin-feng [1]Cen;Xiao-wen [3]He;Ying [4]Lu;Qing-qiang [1]Xu;Kai [1]Xiao

机构地区：[1]Lab of Toxicology and Pharmacology,Faculty of Naval Medicine,Naval Medical University,Shanghai 200433,China;[2]Department of Preventive Medicinne,School of Medicine,Hunan Normal University,Changsha,China;[3]Origincell Technology Group Co.,Ltd.,Shanghai 201203,China;[4]Department of Pharmaceutical Science,School of Pharmacy,Naval Medical University,Shanghai 200433,China

出　　处：《Acta Pharmacologica Sinica》索引2021年第42卷第12期,共12页

基　　金：funded by the National Natural Science Foundation of China(81671858 and 81871521);the Natural Science Foundation of Shanghai(20ZR1470300). 摘　　要：Sulfur mustard(SM)is a highly toxic chemical warfare agent that causes acute lung injury(ALI)and/or acute respiratory distress syndrome(ARDS).There are no effective therapeutic treatments or antidotes available currently to counteract its toxic effects.Our previous study shows that bone marrow-derived mesenchymal stromal cells(BMSCs)could exert therapeutic effects against SM-induced lung injury.In this study,we explored the therapeutic potential of BMSC-derived exosomes(BMSC-Exs)against ALI and the underlying mechanisms.ALI was induced in mice by injection of SM(30 mg/kg,sc)at their medial and dorsal surfaces.BMSC-Exs(20μg/kg in 200μL PBS,iv)were injected for a 5-day period after SM exposure.We showed that BMSC-Exs administration caused a protective effect against pulmonary edema.Using a lung epithelial cell barrier model,BMSC-Exs(10,20,40μg)dose-dependently inhibited SM-induced cell apoptosis and promoted the recovery of epithelial barrier function by facilitating the expression and relocalization of junction proteins(E-cadherin,claudin-1,occludin,and ZO-1).We further demonstrated that BMSC-Exs protected against apoptosis and promoted the restoration of barrier function against SM through upregulating G protein-coupled receptor family C group 5 type A(GPRC5A),a retinoic acid target gene predominately expressed in the epithelial cells of the lung.Knockdown of GPRC5A reduced the antiapoptotic and barrier regeneration abilities of BMSC-Exs and diminished their therapeutic effects in vitro and in vivo.BMSC-Exs-caused upregulation of GPRC5A promoted the expression of Bcl-2 and junction proteins via regulating the YAP pathway.In summary,BMSC-Exs treatment exerts protective effects against SM-induced ALI by promoting alveolar epithelial barrier repair and may be an alternative approach to stem cell-based therapy. 关键词：acute lung injury sulfur mustard BMSC-derived exosomes alveolar epithelial barrier GPRC5A YAP

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BMSC-derived exosomes ameliorate sulfur mustard-induced acute lung injury by regulating the GPRC5A-YAP axis

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