Transplantation Center, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Front Immunol. 2023 Aug 15;14:1162159. doi: 10.3389/fimmu.2023.1162159. eCollection 2023.
Until now, acute respiratory distress syndrome (ARDS) has been a difficult clinical condition with a high mortality and morbidity rate, and is characterized by a build-up of alveolar fluid and impaired clearance. The underlying mechanism is not yet fully understood and no effective medications available. Autophagy activation is associated with ARDS caused by different pathogenic factors. It represents a new direction of prevention and treatment of ARDS to restrain autophagy to a reasonable level through pharmacological and molecular genetic methods. Na, K-ATPase is the main gradient driver of pulmonary water clearance in ARDS and could be degraded by the autophagy-lysosome pathway to affect its abundance and enzyme activity. As a normal growth hormone in human body, insulin has been widely used in clinical for a long time. To investigate the association of insulin with Na, K-ATPase, autophagy and inflammatory markers in LPS-treated C57BL/6 mice by survival assessment, proteomic analysis, histologic examination, inflammatory cell counting, myeloperoxidase, TNF-α and IL-1β activity analysis etc. This was also verified on mouse alveolar epithelial type II (AT II) and A549 cells by transmission electron microscopy. We found that insulin restored the expression of Na, K-ATPase, inhibited the activation of autophagy and reduced the release of inflammatory factors caused by alveolar epithelial damage. The regulation mechanism of insulin on Na, K-ATPase by inhibiting autophagy function may provide new drug targets for the treatment of ARDS.
迄今为止，急性呼吸窘迫综合征（ARDS）一直是一种临床治疗难度大、病死率和病残率高的疾病，其特征是肺泡液体蓄积和清除受损。其潜在机制尚未完全阐明，也没有有效的治疗药物。自噬激活与不同致病因素引起的 ARDS 有关。通过药理学和分子遗传学方法将自噬抑制在合理水平，代表了 ARDS 防治的新方向。Na+、K+-ATP 酶是 ARDS 中肺水清除的主要梯度驱动因素，可通过自噬溶酶体途径降解，影响其丰度和酶活性。胰岛素作为人体正常生长激素，长期以来在临床上得到广泛应用。通过生存评估、蛋白质组学分析、组织学检查、炎症细胞计数、髓过氧化物酶、TNF-α 和 IL-1β 活性分析等方法，研究胰岛素与 LPS 处理的 C57BL/6 小鼠中 Na+、K+-ATP 酶、自噬和炎症标志物的关系，并通过透射电子显微镜在小鼠肺泡上皮 II 型（AT II）和 A549 细胞上进行验证。我们发现胰岛素恢复了 Na+、K+-ATP 酶的表达，抑制了自噬的激活，并减少了肺泡上皮损伤引起的炎症因子的释放。胰岛素通过抑制自噬功能对 Na+、K+-ATP 酶的调节机制可能为 ARDS 的治疗提供新的药物靶点。
