BMSC外泌体lncRNA-ZFAS1通过UPF1/FOXD1轴减轻肺缺血再灌注损伤机制

Abstract

Bone marrow-derived mesenchymal stem cells (BMSCs) exert protective effects against pulmonary ischemia/reperfusion (I/R) injury; however, the potential mechanism involved in their protective ability remains unclear. Thus, this study aimed to explore the function and underlying mechanism of BMSC-derived exosomal lncRNA-ZFAS1 in pulmonary I/R injury. Pulmonary I/R injury models were established in mice and hypoxia/reoxygenation (H/R)-exposed primary mouse lung microvascular endothelial cells (LMECs). Exosomes were extracted from BMSCs. Target molecule expression was assessed by qRT-PCR and Western blotting. Pathological changes in the lungs, pulmonary edema, apoptosis, pro-inflammatory cytokine levels, SOD, MPO activities, and MDA level were measured. The proliferation, apoptosis, and migration of LMECs were detected by CCK-8, EdU staining, flow cytometry, and scratch assay. Dual-luciferase reporter assay, RNA pull-down, RIP, and ChIP assays were performed to validate the molecular interaction. In the mouse model of pulmonary I/R injury, BMSC-Exos treatment relieved lung pathological injury, reduced lung W/D weight ratio, and restrained apoptosis and inflammation, whereas exosomal ZFAS1 silencing abolished these beneficial effects. In addition, the proliferation, migration inhibition, apoptosis, and inflammation in H/R-exposed LMECs were repressed by BMSC-derived exosomal ZFAS1. Mechanistically, ZFAS1 contributed to FOXD1 mRNA decay via interaction with UPF1, thereby leading to Gal-3 inactivation. Furthermore, FOXD1 depletion strengthened the weakened protective effect of ZFAS1-silenced BMSC-Exos on pulmonary I/R injury. ZFAS1 delivered by BMSC-Exos results in FOXD1 mRNA decay and subsequent Gal-3 inactivation via direct interaction with UPF1, thereby attenuating pulmonary I/R injury.