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Endothelial progenitor cell (EPC) has potential to attenuate pulmonary inflammation and injury. As a pivotal paracrine entity of stem cells, whether EPC-derived exosomes (EPC-Exos) contribute to acute lung injury (ALI) remains unknown. Exosomes were purified from conditional medium of EPCs, and then characterized by electron micrograph and immunoblotting. A model of ALI was induced by lipopolysaccharide (LPS) and then rats were transplanted with EPC-Exos. The underlying mechanisms of action of EPC-Exos were examined in vitro endothelial functional assays including the TEER, proliferation (CKK-8), angiogenesis and migration. A possible underlying mechanism was examined by western blotting and further animal studies. Administration of EPC-Exos ameliorated LPS-induced ALI and restored the in vivo pulmonary integrity. EPC-Exos enhanced the proliferation, migration and tube formation of the endothelial cells (ECs). Furthermore, we found that miR-126 was enriched in EPC-Exos and can be delivered onto ECs. Modification of EPCs through miR-126 knockdown can diminish their exosomes function in vitro, indicative of the abilities of EPC-Exos to protect against LPS were inherited by the horizontal shuttled miR-126. Luciferase reporter assays confirmed that miR-126 could target SPRED1. Additionally, the miR-126 transferred to target endothelial cells resulted in subsequent downregulation of SPRED1 and promoted RAF/ERK signaling pathways and subsequent improvement in endothelial cell function. Our study revealed a novel role of exosomal miRNAs in EPC-mediated therapy, suggesting that the clinical application of EPC-Exos might represent a strategy in ALI/ARDS.Administration of EPC-Exos ameliorated LPS-induced ALI and restored the in vivo lung integrity.The microRNA miR-126 was enriched in EPC-Exos and the abilities of EPC-Exos to protect against LPS were relayed by the horizontal shuttled miR-126.Transferred miR-126 to target endothelial cells downregulated SPRED1 and implicated RAF/ERK signaling pathways in the reparative process in rat model of lung injury.