Objective: To investigate the effect of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) on the M1/M2 polarization of alveolar macrophages NR8383 in rats with lipopolysaccharide (LPS)-induced acute lung injury and its potential mechanism. Methods: Bone marrow mesenchymal stem cells were isolated from Sprague-Dawley (SD) rats, and BMSCs-Exos were prepared. NR8383 cells were pretreated with 0.1 or 1 mg/mL BMSCs-Exos for 1 h, followed by induction with 1 μg/mL LPS for 48 h, respectively. ELISA and Western blotting were used to detect the inflammatory factor levels in the cell supernatant and the expression of intracellular polarization marker proteins, respectively. NR8383 cells were cultured alone or co-cultured with BMSCs, treated with 20 μmol/L exosome inhibitor GW4869, and induced with 1 μg/mL LPS for 48 h. Quantitative real-time PCR (qRT-PCR) and Western blotting were used to detect the intracellular miR-212-5p expression and the relative expression of IL-4Rα and p-STAT6 proteins, respectively. The binding site of miR-212-5p and IL-4Rα mRNA were predicted by bioinformatics and verified by luciferase assay. Results: BMSCs-Exos were successfully prepared. ELISA and Western blotting results showed that 1 μg/mL LPS induced for 48 h promoted the secretion of inflammatory factors (TNF-α, IL-1β, and IL-10) and M1 polarization of NR8383 cells. Pretreatment with BMSCs-Exos significantly reduced the contents of LPS-induced inflammatory factors TNF-α and IL-1β, upregulated the content of anti-inflammatory factor IL-10, inhibited M1 polarization and promoted M2 polarization of NR8383 cells, and the effect of 1 mg/mL BMSCs-Exos was significantly stronger than that of 0.1 mg/mL BMSCs-Exos. The cell co-culture experiment results showed that 1 μg/mL LPS induced for 48 h increased miR-212-5p levels and IL-4Rα and p-STAT6 protein expression in NR8383 cells. Co-culture with BMSCs greatly inhibited the effects of LPS on the above indicators, however the effect of BMSCs could be blocked by GW4869. Luciferase assay results indicated that miR-212-5p could bind to the 3′UTR of IL-4Rα mRNA and promote its protein expression. Conclusion: BMSCs-Exos could inhibit M1 polarization and promote M2 polarization of LPS-induced rat alveolar macrophage NR8383 through the miR-212-5p/IL-4Rα/ STAT6 pathway.
［Key words］extracellular vesicles derived from bone marrow mesenchymal cells; acute lung injury; alveolar macrophages; M2 polarization; miR-212-5p

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