【摘 要】
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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 effec
【机 构】
：
Lab of Toxicology and Pharmacology,Faculty of Naval Medicine,Naval Medical University,Shanghai 20043
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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 ALl and the underlying mechanisms.ALl was induced in mice by injection of SM (30 mg/kg,sc) at their medial and dorsal surfaces.BMSC-Exs (20μg/kg in 200 μL 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 (10,20,40 μg) 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 ALl by promoting alveolar epithelial barrier repair and may be an alternative approach to stem cell-based therapy.
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