Mesenchymal Stem Cells Attenuate Acute Lung Injury Through the NF-κB/STAT3-Ntrk2 Axis to Promote Alveolar Epithelial Regeneration.

INTRODUCTION: Mesenchymal stem cells (MSCs) possess immunomodulatory and tissuereparative properties and have shown therapeutic potential in acute lung injury (ALI). However, the mechanisms underlying their protective effects remain unclear. This study aimed to evaluate the effects of MSCs on bleomycin-induced ALI and to explore the underlying molecular mechanisms. METHODS: A bleomycin-induced ALI mouse model was established, followed by human umbilical cord-derived MSC administration. Lung injury, pulmonary edema, neutrophil infiltration, and apoptosis of alveolar type II epithelial cells (AT2) were assessed. RNA-seq and molecular validation were performed using sorted AT2 cells to investigate the underlying mechanism. In vitro assays were carried out to examine the role of Ntrk2 in MSC-mediated epithelial repair. RESULTS: MSC treatment alleviated lung injury, improved alveolar structure, reduced pulmonary edema, and decreased neutrophil infiltration and AT2 cell apoptosis. RNA-seq and molecular analyses indicated that MSCs regulated Ntrk2 expression by suppressing NF-κB signaling and enhancing STAT3 signaling, thereby promoting alveolar epithelial regeneration. In vitro, inhibition of Ntrk2 impaired the promotive effects of MSCs on A549 cell migration and alveolar organoid repair. DISCUSSION: These findings suggest that MSCs protect against ALI by attenuating inflammatory injury and promoting alveolar epithelial repair, with the NF-κB/STAT3-Ntrk2 axis contributing to this process. CONCLUSION: MSC treatment ameliorated bleomycin-induced ALI and promoted alveolar epithelial regeneration, at least partly through the NF-κB/STAT3-Ntrk2 axis. These results provide further mechanistic support for MSC-based therapy in ALI.