Huang Dou, Ju Feng, Du Lei, Liu Ting, Zuo Yunxia, Abbott Geoffrey W, Hu Zhaoyang
Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.).
Department of Anesthesiology (D.H., L.D., Y.Z.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology (F.J., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China; and Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (G.W.A.)
J Pharmacol Exp Ther. 2022 Mar;380(3):230-241. doi: 10.1124/jpet.121.000956. Epub 2021 Dec 10.
Ischemia/reperfusion (I/R) injury of the lung can lead to extensive pulmonary damage. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are insulin-independent, oral antihyperglycemic agents used for treating type 2 diabetes mellitus (T2DM). Although their cardioprotective properties have been reported, their potential roles in pulmonary protection in vivo are poorly characterized. Here, we tested a hypothesis that empagliflozin, an SGLT2 inhibitor, can protect lungs in a mouse model of lung I/R injury induced by pulmonary hilum ligation in vivo. We assigned C57/BL6 mice to sham-operated, nonempagliflozin-treated control, or empagliflozin-treated groups. Pulmonary I/R injury was induced by 1-hour left hilum ligation followed by 2-hour reperfusion. Using quantitative polymerase chain reaction (q-PCR) and Western blot analysis, we demonstrate that SGLT2 is highly expressed in mouse kidney but is weakly expressed in mouse lung ( = 5-6 per group, < 0.01 or < 0.001). Empagliflozin improved respiratory function, attenuated I/R-induced lung edema, lessened structural damage, inhibited apoptosis, and reduced inflammatory cytokine production and protein concentration in bronchoalveolar lavage (BAL) fluid [ < 0.05 or < 0.001 versus control group (CON)]. In addition, empagliflozin enhanced phosphorylation of pulmonary extracellular signal-regulated kinases 1 and 2 (ERK1/2) post-I/R injury in vivo ( < 0.001, versus CON, = 5 per group). We further showed that pharmacological inhibition of ERK1/2 activity reversed these beneficial effects of empagliflozin. In conclusion, we showed that empagliflozin exerts strong lung protective effects against pulmonary I/R injury in vivo, at least in part via the ERK1/2-mediated signaling pathway. SIGNIFICANCE STATEMENT: Pulmonary ischemia-reperfusion (I/R) can exacerbate lung injury. Empagliflozin is a new antidiabetic agent for type 2 diabetes mellitus. This study shows that empagliflozin attenuates lung damage after pulmonary I/R injury in vivo. This protective phenomenon was mediated at least in part via the extracellular signal-regulated kinases 1 and 2-mediated signaling pathway. This opens a new avenue of research for sodium-glucose cotransporter-2 inhibitors in the treatment of reperfusion-induced acute pulmonary injury.
肺缺血/再灌注（I/R）损伤可导致广泛的肺损伤。钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂是一类非胰岛素依赖型口服降糖药，用于治疗2型糖尿病（T2DM）。尽管已有报道称其具有心脏保护作用，但其在体内肺保护方面的潜在作用仍未得到充分研究。在此，我们验证了一个假设，即SGLT2抑制剂恩格列净可在体内肺门结扎诱导的肺I/R损伤小鼠模型中保护肺组织。我们将C57/BL6小鼠分为假手术组、未用恩格列净治疗的对照组或恩格列净治疗组。通过结扎左肺门1小时后再灌注2小时诱导肺I/R损伤。使用定量聚合酶链反应（q-PCR）和蛋白质免疫印迹分析，我们发现SGLT2在小鼠肾脏中高表达，但在小鼠肺组织中低表达（每组n = 5 - 6，P < 0.01或P < 0.001）。恩格列净改善了呼吸功能，减轻了I/R诱导的肺水肿，减少了结构损伤，抑制了细胞凋亡，并降低了支气管肺泡灌洗（BAL）液中炎性细胞因子的产生和蛋白浓度[与对照组（CON）相比，P < 0.05或P < 0.001]。此外，恩格列净在体内I/R损伤后增强了肺细胞外信号调节激酶1和2（ERK1/2）的磷酸化水平（P < 0.001，与CON组相比，每组n = 5）。我们进一步表明，药理学抑制ERK1/2活性可逆转恩格列净的这些有益作用。总之，我们发现恩格列净在体内对肺I/R损伤具有强大的肺保护作用，至少部分是通过ERK1/2介导的信号通路实现的。意义声明：肺缺血-再灌注（I/R）可加重肺损伤。恩格列净是一种用于治疗2型糖尿病的新型抗糖尿病药物。本研究表明，恩格列净可减轻体内肺I/R损伤后的肺损伤。这种保护现象至少部分是通过细胞外信号调节激酶1和2介导的信号通路介导的。这为钠-葡萄糖协同转运蛋白2抑制剂治疗再灌注诱导的急性肺损伤开辟了一条新的研究途径。
