Pulmonary microvascular endothelial cells (PMVECs) barrier dysfunction is a main pathophysiological feature of sepsis-related acute lung injury (ALI). This study aimed to investigate whether the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin could protect against LPS-induced PMVECs barrier disruption and its underlying molecular mechanisms. A classical ALI animal model and LPS-treated PMVECs were applied and all were treated with or without linagliptin. Cellular experiments demonstrated that linagliptin could mitigate LPS-induced PMVECs hyperpermeability and intercellular junction (VE-cadherin, β-catenin, and ZO-1) disruption in a dose-dependent manner. Correspondingly, it was observed that linagliptin pretreatment distinctly relieved LPS-induced lung injury, oxidative stress, and pulmonary edema in vivo. Furthermore, we found that the inhibition of oxidative stress by linagliptin may be achieved by reversing impaired mitochondrial function. Mechanistically, linagliptin administration promoted the activation of the Epac1 pathway and its downstream AKT pathway, while inhibition of the Epac1/Akt signaling pathway significantly alleviated the above-mentioned protective effect of linagliptin on the PMVECs barrier. Taken together, these data suggest that linagliptin can effectively reserve PMVECs barrier dysfunction and inhibit oxidative stress to protect against ALI via activating the Epac1/AKT signaling pathway, and thus may become a potential clinical therapeutic strategy for ALI.

肺微血管内皮细胞 (PMVECs) 屏障功能障碍是脓毒症相关急性肺损伤 (ALI) 的主要病理生理特征。本研究旨在探讨二肽基肽酶 (DPP)-4 抑制剂利格列汀是否可以防止 LPS 诱导的 PMVECs 屏障破坏及其潜在的分子机制。应用经典的 ALI 动物模型和经 LPS 处理的 PMVEC，并且均使用或不使用利格列汀进行处理。细胞实验表明，利格列汀可以以剂量依赖的方式减轻 LPS 诱导的 PMVECs 高渗透性和细胞间连接（VE-钙粘蛋白、β-连环蛋白和 ZO-1）破坏。相应地，观察到利格列汀预处理显着缓解了体内LPS诱导的肺损伤、氧化应激和肺水肿。此外，我们发现利格列汀对氧化应激的抑制作用可以通过逆转受损的线粒体功能来实现。机制上，利格列汀给药促进了 Epac1 通路及其下游 AKT 通路的激活，而抑制 Epac1/Akt 信号通路显着减轻了上述利格列汀对 PMVECs 屏障的保护作用。综上所述，这些数据表明，利格列汀可通过激活 Epac1/AKT 信号通路有效地保留 PMVECs 屏障功能障碍并抑制氧化应激以预防 ALI，因此可能成为 ALI 潜在的临床治疗策略。利格列汀给药促进了 Epac1 通路及其下游 AKT 通路的激活，而抑制 Epac1/Akt 信号通路则显着减轻了上述利格列汀对 PMVECs 屏障的保护作用。综上所述，这些数据表明，利格列汀可通过激活 Epac1/AKT 信号通路有效地保留 PMVECs 屏障功能障碍并抑制氧化应激以预防 ALI，因此可能成为 ALI 潜在的临床治疗策略。利格列汀给药促进了 Epac1 通路及其下游 AKT 通路的激活，而抑制 Epac1/Akt 信号通路则显着减轻了上述利格列汀对 PMVECs 屏障的保护作用。综上所述，这些数据表明，利格列汀可通过激活 Epac1/AKT 信号通路有效地保留 PMVECs 屏障功能障碍并抑制氧化应激以预防 ALI，因此可能成为 ALI 潜在的临床治疗策略。