Empagliflozin Protects against Pulmonary Ischemia/Reperfusion Injury via an ERK1/2-Dependent Mechanism.

Ischemia/reperfusion (I/R) injury of the lung can lead to extensive pulmonary damage. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are insulin-independent, oral anti-hyperglycemic agents used for treating type 2 diabetes mellitus (T2DM). Their cardioprotective properties have been reported, however, their potential roles in pulmonary protection in vivo are poorly characterized. Here, we tested an 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, non-empagliflozin-treated control, or empagliflozin-treated groups. Pulmonary I/R injury was induced by 1-hour left hilum ligation followed by 2-hour reperfusion. Using q-PCR and western blot analysis, we demonstrate that SGLT2 is highly expressed in mouse kidney but is weakly expressed in mouse lung (n=5-6 per group, P<0.01 or P<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 (P<0.05 or P<0.001 vs. CON). In addition, empagliflozin enhanced phosphorylation of pulmonary ERK1/2 post-I/R injury in vivo (P<0.001, vs. CON, n=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 anti-diabetic 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 ERK1/2-mediated signaling pathway. This opens a new avenue of research for SGLT2 inhibitors in the treatment of reperfusion-induced acute pulmonary injury.