Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Promote M2 Polarization and Protect Against Acute Lung Injury.

The purpose of this research is to elucidate the molecular mechanisms by which bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) improve acute lung injury (ALI) through the regulation of alveolar macrophage polarization. BMSCs-Exos were prepared and used to pretreat mouse alveolar macrophages (MH-S), followed by stimulation with LPS and IFN-γ. The binding interaction between miR-137-3p and the 3' untranslated region (3'UTR) of TRIM24 mRNA was confirmed through luciferase reporter assays. BMSCs-Exos were used to treat MH-S cells stimulated with LPS and IFN-γ, then TRIM24 protein expression, STAT6 acetylation, and reactive oxygen species (ROS) production were analyzed, along with the mRNA levels of macrophage polarization-related genes. The ALI mouse model was established by intratracheal instillation of LPS, followed by intratracheal administration of BMSCs-Exos. Subsequently, lung histopathology, pulmonary function, wet-to-dry weight ratio and the levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were evaluated. LPS and IFN-γ stimulation significantly increased the levels of TNF-α, IL-1β, and IL-10 in culture supernatants, as well as CD86 and CD163 mRNA expressions in MH-S cells. Treatment with BMSCs-Exos significantly decreased TNF-α, IL-1β, and CD86 levels while increasing CD163 and IL-10 levels. MiR-137-3p inhibits TRIM24 protein expression by binding to the 3'UTR of its mRNA. BMSCs upregulated miR-137-3p and suppressed TRIM24 protein expression in MH-S cells co-cultured with BMSCs, effects that were abolished by GW4869 treatment or by silencing miR-137-3p in BMSCs. In LPS and IFN-y-induced MH-S cells, treatment with BMSCs-Exos effectively upregulated miR-137-3p levels and downregulated the TRIM24 expression, which in turn promoted the expression of M2 polarization-related genes Arg1 and Fizz1, while inhibiting the expression of the M1 polarization gene Nos2 and reducing ROS production. In vivo, intratracheal administration of BMSCs-Exos alleviated pulmonary inflammation and injury in ALI mice and enhanced M2 polarization of alveolar macrophages. BMSCs-Exos promote M2 polarization and inhibit M1 polarization of alveolar macrophages by delivering miR-137-3p, thereby significantly improving lung injury.