BMSCs-exo源lncRNA SNHG12经miR-140-3p/HOXA9轴抑制有氧糖酵解调控肺泡巨噬细胞极化减轻脓毒症相关ARDS

脓毒症相关急性呼吸窘迫综合征(ARDS)治疗困难，病死率高。有氧糖酵解增强引起的肺泡巨噬细胞(AMs)极化失衡是其重要发病机制。我们前期证实骨髓间充质干细胞外泌体(BMSCs-exo)可减轻脓毒症相关ARDS，但机制不明。预实验发现BMSCs-exo可抑制脓毒症时AMs糖酵解相关酶表达及乳酸生成，这与其携带的lncRNA SNHG12减弱AMs内miR-140-3p对HOXA9的抑制有关。由此我们推测BMSCs-exo转运lncRNA SNHG12至AMs，竞争性结合miR-140-3p而上调HOXA9表达，进而抑制AMs有氧糖酵解并调控其极化，减轻脓毒症相关ARDS。本课题拟采用小鼠腹腔注射LPS模型和LPS刺激AMs模型，结合基因沉默及过表达等技术验证上述假说，以期从lncRNA调控AMs糖代谢角度揭示BMSCs-exo缓解脓毒症相关ARDS的机制，为治疗脓毒症相关ARDS提供新思路。

Sepsis-associated acute respiratory distress syndrome (ARDS) is a difficult condition to treat and is often associated with a high mortality rate. Previous studies showed that enhanced aerobic glycolysis promotes the imbalance of alveolar macrophages polarization, which is an important pathogenesis of sepsis-associated ARDS. We have found that bone marrow mesenchymal stem cells-derived exosome (BMSCs-exo) could alleviate sepsis-associated ARDS, but the mechanism remains unclear. Our preliminary experiments showed that BMSCs-exo could suppress the expression of glycolytic enzymes and inhibit the production of lactate in alveolar macrophages during sepsis, which might be due to the BMSCs-derived exosomal lncRNA SNHG12 reducing the inhibitory effect of miR-140-3p on HOXA9 in alveolar macrophages. Therefore, we hypothesized that exosomal lncRNA SNHG12 derived from BMSCs could be transferred to alveolar macrophages and suppress aerobic glycolysis via competitively binding miR-140-3p to facilitate HOXA9 expression, subsequently resulting in dynamic regulation of alveolar macrophages polarization and attenuating sepsis-associated ARDS. In the present study, we will establish the mouse experimental sepsis model by intraperitoneal injection of LPS and LPS-stimulated alveolar macrophages model, gene silencing and overexpression techniques will be applied to verify the above hypothesis. The purpose of this study is to explore the mechanism of BMSCs-exo in alleviating sepsis-associated ARDS from the perspective of lncRNA regulating glucose metabolism in alveolar macrophages. The present study may provide a novel strategy for the clinical treatment of sepsis-associated ARDS.