Abstract
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 (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 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 (P < 0.001, versus 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 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.
Highlights
Pulmonary ischemia-reperfusion (I/R) occurs in many clinical conditions
There were another three parallel experiments to evaluate the beneficial effects of empagliflozin against lung I/R injury. 34 mice were used for the determination of wet-to-dry ratio and oxygenation. 25 mice were used for histological staining, transferase-mediated dUTP nick-end labeling (TUNEL) analysis and western blot analysis. 15 mice were used for Inflammatory cytokines and myeloperoxidase measurements
We found that U0126 induced pulmonary apoptosis, such that inhibitor-treated lungs in the empagliflozin group had more TUNEL-stained nuclei when compared to non-inhibitor-treated empagliflozin lungs (P
Summary
Pulmonary ischemia-reperfusion (I/R) occurs in many clinical conditions (de Perrot et al, 2003; Chen-Yoshikawa, 2021) This process is often associated with an exacerbation of lung injury, leading to heavy deterioration in lung function and altered lung histological structure (de Perrot et al, 2003). Empagliflozin, dapagliflozin, canagliflozin and ertugliflozin are recently developed anti-diabetic agents used in the clinical management of type 2 diabetes mellitus (T2DM) They reduce plasma glucose concentrations via regulating glucose homeostasis (Jurczak et al, 2011). Empagliflozin was shown to limit infarct size after myocardial ischemia/reperfusion injury (Lu et al, 2020), the question has remained unanswered whether empagliflozin has beneficial effects against reperfusion-induced lung injury It is worth exploring the underlying molecular mechanisms in potential pulmonary-protective effects with the goal of developing novel and effective therapeutic approaches to ameliorate lung damage after pulmonary I/R injury in the postoperative period
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