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MicroRNA-503-5p-Enriched Extracellular Vehicles Promotes Acute Lung Injury in Rats with Severe Acute Pancreatitis By Targeting RECK and Regulating the JAK/STAT3/GPX4 Pathway
57 Pages Posted: 19 Mar 2025
More...Abstract
Background: Acute lung injury (ALI) is complicated in severe acute pancreatitis (SAP). MiR-503-5p is identified as a critical regulatory miRNA in extracellular vesicles extracted from blood samples of patients with SAP-associated ALI. This study elucidates the roles and molecular mechanisms of exosomal miR-503-5p in SAP-associated ALI.
Methods: SAP was induced through retrograde injection of 5% sodium taurocholate into the biliopancreatic duct. The in vivo effect of miR-503-5p depletion was examined via hematoxylin and eosin staining, serum detection, immunohistochemical staining, RT-qPCR, ELISA, TEM, DHE staining, MDA and GSH detection, western blotting, and immunofluorescence staining. Exosomes were isolated from rat plasma and cocultured with BEAS-2B cells. The in vitro function of miR-503-5p was examined using ELISA, CCK-8 assays, immunofluorescence staining, DCFH-DA staining, Fe2+, MDA, and GSH measurement, western blotting, and luciferase reporter assays were performed.
Results: SAP-Exo promoted inflammation and ferroptosis in BEAS-2B cells, and miR-503-5p was enriched in SAP-Exo. Reduction of miR-503-5p or ferroptosis attenuated the effect of SAP-Exo on enhancing inflammation and ferroptosis. Mechanistically, miR-503-5p targeted RECK 3’UTR. RECK silencing restrained the miR-503-5p inhibitor-induced reduction in inflammation and ferroptosis. For in vivo analysis, miR-503-5p depletion alleviated SAP-induced lung injury and suppressed SAP-induced inflammation and ferroptosis in lung tissues. Moreover, miR-503-5p regulated the JAK2/STAT3 pathway by targeting RECK, and JAK2 activation counteracted the protective effect of miR-503-5p inhibition.
Conclusion: MiR-503-5p is upregulated in circulating exosomes isolated from SAP rat plasma and can be transported to pulmonary epithelial cells, where it targets RECK to activate JAK2/STAT3 signaling, thereby promoting inflammation and ferroptosis and ALI.
Keywords: severe acute pancreatitis, acute lung injury, exosomes, miR-503-5p, RECK, ferroptosis, inflammation, JAK2/STAT3
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