Hydrogen Sulfide Ameliorates Lung Ischemia-Reperfusion Injury Through SIRT1 Signaling Pathway in Type 2 Diabetic Rats.

Weiwei Yang,Tianhua Liu,Zhiqiang Song,Tao Jiang,Xiangqi Lv,Hongli Zhang

doi:10.3389/fphys.2020.00596

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 (H2S) protected against diabetic lung IR injury by suppressing oxidative damage. This study aimed to examine the mechanism by which H2S affects diabetic lung IR injury. High-fat-diet-fed streptozotocin-induced type 2 diabetic rats were exposed to GYY4137, a slow-releasing H2S 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.

Highlights

The prevalence of diabetes is dramatically increasing across all age groups around the world (Chen et al, 2011)
We have demonstrated that diabetes mellitus (DM) aggravated lung IR insult and that enhanced oxidative stress played a crucial role in diabetic lung IR insult (Song et al, 2017; Jiang et al, 2019)
The PaO2/FiO2 (T7) values in the DM + IR group showed a further decrease compared with the Con + IR group (P < 0.01)

Summary

Introduction

The prevalence of diabetes is dramatically increasing across all age groups around the world (Chen et al, 2011). Under the diabetic condition, sustained hyperglycemia dramatically induces reactive oxygen species (ROS) overproduction and impairs antioxidant defenses, thereby aggravating oxidative stress and causing cell necrosis and apoptosis (Evans et al, 2002; Zheng et al, 2017). Oxidative stress and inflammation play key roles in the processes of apoptosis, which may account for the poor outcome in diabetic patients following lung transplantation (Hackman et al, 2014). We have demonstrated that DM aggravated lung IR insult and that enhanced oxidative stress played a crucial role in diabetic lung IR insult (Song et al, 2017; Jiang et al, 2019).

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