Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
Int J Mol Sci. 2022 Mar 12;23(6):3065. doi: 10.3390/ijms23063065.
The pathophysiology of sepsis involves inflammation and hypercoagulability, which lead to microvascular thrombosis and compromised organ perfusion. Dipeptidyl peptidase (DPP)-4 inhibitors, e.g., linagliptin, are commonly used anti-diabetic drugs known to exert anti-inflammatory effects. However, whether these drugs confer an anti-thrombotic effect that preserves organ perfusion in sepsis remains to be investigated. In the present study, human umbilical vein endothelial cells (HUVECs) were treated with linagliptin to examine its anti-inflammatory and anti-thrombotic effects under tumor necrosis factor (TNF)-α treatment. To validate findings from in vitro experiments and provide in vivo evidence for the identified mechanism, a mouse model of lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome was used, and pulmonary microcirculatory thrombosis was measured. In TNF-α-treated HUVECs and LPS-injected mice, linagliptin suppressed expressions of interleukin-1β (IL-1β) and intercellular adhesion molecule 1 (ICAM-1) via a nuclear factor-κB (NF-κB)-dependent pathway. Linagliptin attenuated tissue factor expression via the Akt/endothelial nitric oxide synthase pathway. In LPS-injected mice, linagliptin pretreatment significantly reduced thrombosis in the pulmonary microcirculation. These anti-inflammatory and anti-thrombotic effects were independent of blood glucose level. Together the present results suggest that linagliptin exerts protective effects against endothelial inflammation and microvascular thrombosis in a mouse model of sepsis.
脓毒症的病理生理学涉及炎症和高凝状态,这导致微血管血栓形成和器官灌注受损。二肽基肽酶-4 抑制剂(如利拉利汀)是常用的抗糖尿病药物,已知具有抗炎作用。然而,这些药物是否具有抗血栓作用,从而维持脓毒症中的器官灌注仍有待研究。在本研究中,用人脐静脉内皮细胞(HUVEC)处理利拉利汀,以研究其在肿瘤坏死因子(TNF)-α处理下的抗炎和抗血栓作用。为了验证体外实验的结果,并为所确定的机制提供体内证据,使用了脂多糖(LPS)诱导的全身炎症反应综合征的小鼠模型,并测量了肺微循环血栓形成。在 TNF-α处理的 HUVEC 和 LPS 注射的小鼠中,利拉利汀通过核因子-κB(NF-κB)依赖性途径抑制白细胞介素-1β(IL-1β)和细胞间黏附分子 1(ICAM-1)的表达。利拉利汀通过 Akt/内皮型一氧化氮合酶途径抑制组织因子的表达。在 LPS 注射的小鼠中,利拉利汀预处理显著减少了肺微循环中的血栓形成。这些抗炎和抗血栓作用与血糖水平无关。总之,这些结果表明,利拉利汀在脓毒症小鼠模型中对内皮炎症和微血管血栓形成具有保护作用。