FGF21抑制NLRP3炎症小体通路减轻机械通气肺损伤的作用及机制

Ventilator-induced lung injury (VILI) is a difficult issue in clinical anesthesia and treatment of critical patients. Previous studies have shown that VILI is closely related to excessive activation of inflammation in lung. Fibroblast growth factor 21 (FGF21) is a metabolic regulator which is secreted into the blood by the liver, but the role of FGF21 in lung and VILI is unknown. In our preliminary work, we found that the blood FGF21 concentration in the VILI mice increased significantly compared with control mice. In the lung microvascular endothelial cells (LMVECs) exposed to mechanical stress (MS), FGF21 was able to alleviate MS-induced damage and inhibit the activation of NLRP3 inflammasome activation. Therefore, we hypothesize that FGF21 may protect against VILI by inhibiting the activition of NLRP3 inflammasome. We intend to further investigate the potential therapeutic effects of FGF21 on VILI models using FGF21 knockout mice and siRNA-mediated knockdown mice. In addition, we will continue to study whether FGF21 reduces VILI-induced damage by inhibiting NLRP3 inflammasome activation and if so, to explore how it affects NLRP3 inflammasome activation. Finally, we will screen the possible signal pathways by which FGF21 regulates NLRP3 and further verify them in animal model. These studies may provide new protection strategy for VILI and shed light on new therapeutic targets for treatment of VILI.

机械通气肺损伤(VILI)是临床麻醉和危重患者救治中面临的棘手难题，其与肺内炎症过度激活密切相关。成纤维细胞生长因子21(FGF21)是由肝脏分泌入血的代谢调控因子，但与肺及VILI关系不明。我们前期研究发现：VILI模型小鼠血中FGF21明显升高；在肺血管内皮细胞上给予FGF21，可减轻机械牵张(MS)导致的细胞活力下降，并伴随着对NLRP3炎症小体通路的显著抑制。据此我们推测：FGF21可能通过抑制NLRP3减轻VILI。本课题拟在FGF21基因敲除小鼠和siRNA干扰小鼠上探索FGF21缺失是否影响VILI的发生发展；在MS细胞和VILI动物模型上明确重组FGF21的治疗效果及其是否依赖于对NLRP3炎症小体的抑制；在细胞模型上筛选FGF21调控NLRP3的信号通路，并在动物模型上进行验证。本研究有望发现基于FGF21-NLRP3通路的VILI保护新策略，具有重要的科学和临床意义。