Abstract
Lung ischemia-reperfusion (IR) injury remains a significant factor for the early mortality of lung transplantations. Diabetes mellitus (DM) is an independent risk factor for 5-year mortality following lung transplantation. Our previous study showed that DM aggravated lung IR injury and that oxidative stress played a key role in this process. Previously, we demonstrated that hydrogen sulfide (H(2)S) protected against diabetic lung IR injury by suppressing oxidative damage. This study aimed to examine the mechanism by which H(2)S affects diabetic lung IR injury. High-fat-diet-fed streptozotocin-induced type 2 diabetic rats were exposed to GYY4137, a slow-releasing H(2)S donor with or without administration of EX527 (a SIRT1 inhibitor), and then subjected to a surgical model of IR injury of the lung. Lung function, oxidative stress, cell apoptosis, and inflammation were assessed. We found that impairment of lung SIRT1 signaling under type 2 diabetic conditions was further exacerbated by IR injury. GYY4137 treatment markedly activated SIRT1 signaling and ameliorated lung IR injury in type 2 DM animals by improving lung functional recovery, diminishing oxidative damage, reducing inflammation, and suppressing cell apoptosis. However, these effects were largely compromised by EX527. Additionally, treatment with GYY4137 significantly activated the Nrf2/HO-1 antioxidant signaling pathway and increased eNOS phosphorylation. However, these effects were largely abolished by EX527. Together, our results indicate that GYY4137 treatment effectively attenuated lung IR injury under type 2 diabetic conditions via activation of lung SIRT1 signaling. SIRT1 activation upregulated Nrf2/HO-1 and activated the eNOS-mediated antioxidant signaling pathway, thus reducing cell apoptosis and inflammation and eventually preserving lung function.