Sulfur mustard (SM) is a blister‐producing chemical warfare agent which could lead to a cascade of systemic damage, especially severe acute lung injury. Oxidative stress is considered to be vital processes for the SM toxicity mechanism. We previously proved the therapeutic effect of exosomes derived from bone marrow mesenchymal stromal cells in promoting the repair of alveolar epithelial barrier and inhibiting apoptosis. However, the key functional components in exosomes and the underlying mechanisms have not been fully elaborated. This research shed light on the function of the key components of human umbilical cord mesenchymal stem cell‐derived exosomes (HMSCs‐Ex). We noted that HMSCs‐Ex‐derived miR‐199a‐5p played a vital role in reducing pneumonocyte oxidative stress and apoptosis by reducing reactive oxygen species, lipid peroxidation products and increasing the activities of antioxidant enzymes in BEAS‐2B cells and mouse models after exposure to SM for 24 h. Furthermore, we demonstrated that the overexpression of miR‐199a‐5p in HMSCs‐Ex treatment induced a further decrease of Caveolin1 and the activation of the mRNA and protein level of NRF2, HO1 and NQO1, compared with HMSCs‐Ex administration. In summary, miR‐199a‐5p was one of the key molecules in HMSCs‐Ex that attenuated SM‐associated oxidative stress via regulating CAV1/NRF2 signalling pathway.

Background Sulfur mustard (SM) is a highly toxic chemical warfare agent that has caused numerous casualties during wars and conflicts in the past century. Specific antidotes or therapeutic strategies are rare due to the complicated mechanism of toxicity, which still awaits elucidation. Clinical data show that acute lung injury (ALI) is responsible for most mortality and morbidity after SM exposure. Extracellular vesicles are natural materials that participate in intercellular communication by delivering various substances and can be modified. In this study, we aim to show that extracellular vesicles derived from human umbilical cord mesenchymal stromal cells (hucMSC-EVs) could exert therapeutic effects on SM-induced ALI, and to explain the underlying mechanism of effects. Methods MiR-146a-5p contained in hucMSC-EVs may be involved in the process of hucMSC-EVs modulating the inflammatory response to SM-induced ALI. We utilized miR-146a-5p delivered by extracellular vesicles and further modified hucMSCs with a miR-146a-5p mimic or inhibitor to collect miR-146a-5p-overexpressing extracellular vesicles (miR-146a-5p+-EVs) or miR-146a-5p-underexpressing extracellular vesicles (miR-146a-5p−-EVs), respectively. Through in vivo and in vitro experiments, we investigated the mechanism. Results The effect of miR-146a-5p+-EVs on improving the inflammatory reaction tied to SM injury was better than that of hucMSC-EVs. We demonstrated that miR-146a-5p delivered by hucMSC-EVs targeted TRAF6 to negatively regulate inflammation in SM-induced ALI models in vitro and in vivo. Conclusion In summary, miR-146a-5p delivered by hucMSC-EVs targeted TRAF6, causing hucMSC-EVs to exert anti-inflammatory effects in SM-induced ALI; thus, hucMSC-EVs treatment may be a promising clinical therapeutic after SM exposure. Graphical Abstract

Background: Sulfur mustard (SM) is a blister-producing chemical warfare agent which could lead to a cascade of systemic damage, especially severe acute lung injury. Oxidative stress is considered to be vital processes for the SM toxicity mechanism. We previously proved the therapeutic effect of exosomes derived from bone marrow mesenchymal stromal cells in promoting the repair of alveolar epithelial barrier and inhibiting apoptosis. However, the key functional components in exosomes and the underlying mechanisms have not been fully elaborated. This research shed light on the function of the key components of human umbilical cord mesenchymal stem cell-derived exosomes. Results: We noted that HMSCs-Ex showed better antioxidant abilities to attenuate SM-induced apoptosis. Furthermore, it was identified that HMSCs-Ex-derived miR-199a-5p played the vital role in reducing pneumonocyte oxidative stress. We observed that the overexpression of miR-199a-5p in HMSCs-Ex exerted protective effects against SM-induced oxidative injury by activating the NRF2 signaling pathway. Moreover, it was confirmed that Caveolin1 (CAV1) was the target gene regulated by miR-199a-5p. MiR-199a-HMSCs-Ex reduced CAV1 expression, leading to the upregulation of NRF2 and the activation of the NRF2 antioxidant signal pathway.Conclusions: MiR-199a-5p was one of the key molecules in HMSCs-Ex that attenuated SM-associated oxidative stress via regulating CAV1/NRF2 signaling pathway.