Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
PLoS One. 2024 May 15;19(5):e0292628. doi: 10.1371/journal.pone.0292628. eCollection 2024.
Hepatic ischemia-reperfusion injury causes liver damage during surgery. In hepatic ischemia-reperfusion injury, the blood coagulation cascade is activated, causing microcirculatory incompetence and cellular injury. Coagulation factor Xa (FXa)- protease-activated receptor (PAR)-2 signaling activates inflammatory reactions and the cytoprotective effect of FXa inhibitor in several organs. However, no studies have elucidated the significance of FXa inhibition on hepatic ischemia-reperfusion injury. The present study elucidated the treatment effect of an FXa inhibitor, edoxaban, on hepatic ischemia-reperfusion injury, focusing on FXa-PAR-2 signaling. A 60 min hepatic partial-warm ischemia-reperfusion injury mouse model and a hypoxia-reoxygenation model of hepatic sinusoidal endothelial cells were used. Ischemia-reperfusion injury mice and hepatic sinusoidal endothelial cells were treated and pretreated, respectively with or without edoxaban. They were incubated during hypoxia/reoxygenation in vitro. Cell signaling was evaluated using the PAR-2 knockdown model. In ischemia-reperfusion injury mice, edoxaban treatment significantly attenuated fibrin deposition in the sinusoids and liver histological damage and resulted in both anti-inflammatory and antiapoptotic effects. Hepatic ischemia-reperfusion injury upregulated PAR-2 generation and enhanced extracellular signal-regulated kinase 1/2 (ERK 1/2) activation; however, edoxaban treatment reduced PAR-2 generation and suppressed ERK 1/2 activation in vivo. In the hypoxia/reoxygenation model of sinusoidal endothelial cells, hypoxia/reoxygenation stress increased FXa generation and induced cytotoxic effects. Edoxaban protected sinusoidal endothelial cells from hypoxia/reoxygenation stress and reduced ERK 1/2 activation. PAR-2 knockdown in the sinusoidal endothelial cells ameliorated hypoxia/reoxygenation stress-induced cytotoxicity and suppressed ERK 1/2 phosphorylation. Thus, edoxaban ameliorated hepatic ischemia-reperfusion injury in mice by protecting against micro-thrombosis in sinusoids and suppressing FXa-PAR-2-induced inflammation in the sinusoidal endothelial cells.
肝缺血再灌注损伤会导致手术过程中的肝损伤。在肝缺血再灌注损伤中，凝血级联反应被激活，导致微循环功能障碍和细胞损伤。凝血因子 Xa（FXa）-蛋白酶激活受体（PAR）-2 信号激活炎症反应和 FXa 抑制剂在几个器官中的细胞保护作用。然而，尚无研究阐明 FXa 抑制对肝缺血再灌注损伤的意义。本研究阐明了 FXa 抑制剂依度沙班对肝缺血再灌注损伤的治疗作用，重点研究了 FXa-PAR-2 信号。使用 60 分钟肝部分暖缺血再灌注损伤小鼠模型和肝窦内皮细胞缺氧/复氧模型。对缺血再灌注损伤小鼠和肝窦内皮细胞分别进行依度沙班处理和预处理，然后在体外进行缺氧/复氧孵育。使用 PAR-2 敲低模型评估细胞信号。在缺血再灌注损伤小鼠中，依度沙班治疗显著减轻了窦内纤维蛋白沉积和肝组织损伤，并具有抗炎和抗凋亡作用。肝缺血再灌注损伤上调 PAR-2 的产生并增强细胞外信号调节激酶 1/2（ERK 1/2）的激活；然而，依度沙班治疗减少了体内 PAR-2 的产生并抑制了 ERK 1/2 的激活。在肝窦内皮细胞的缺氧/复氧模型中，缺氧/复氧应激增加了 FXa 的产生并诱导了细胞毒性作用。依度沙班保护窦内皮细胞免受缺氧/复氧应激，并减少 ERK 1/2 的激活。窦内皮细胞中的 PAR-2 敲低改善了缺氧/复氧应激诱导的细胞毒性并抑制了 ERK 1/2 的磷酸化。因此，依度沙班通过保护窦内微血栓形成和抑制 FXa-PAR-2 诱导的窦内皮细胞炎症来改善小鼠的肝缺血再灌注损伤。
