Takiguchi Makoto, Totsuka Eishi, Umehara Minoru, Ono Hiroaki, Nara Masaki, Nozaki Tsuyoshi, Wajima Naoki, Takahashi Katsuro, Narumi Shunji, Hakamada Kenichi, Sugai Michihiro, Sasaki Mutsuo
Second Department of Surgery, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562 Japan.
Hepatogastroenterology. 2003 May-Jun;50(51):789-93.
BACKGROUND/AIMS: Inflammatory cytokines, such as interleukin-1 beta and tumor necrosis factor-alpha, which activate neutrophils, contribute to hepatic warm ischemia-reperfusion injury. However, the role of the cytokines in hepatic microcirculation immediately after reperfusion is still unclear. This study was carried out to investigate whether FR167653, a dual inhibitor of interleukin-1 beta and tumor necrosis factor-alpha, attenuates hepatic microcirculatory disturbance at the initial phase of reperfusion following liver ischemia.
Adult mongrel dogs were subjected to 90 minutes of liver ischemia by a Pringle's maneuver under portosystemic bypass. The animals were divided into two groups: a control group (n = 10), subjected to hepatic warm ischemia only, and a FR167653 administered group (n = 5), which received 1 mg/kg/h FR167653 for 4 hours since 30 minutes before the ischemia to 2 hours after the reperfusion continuously. Seven days animal survival, hepatic tissue blood flow, liver function test, hepatic venous blood concentration of endothelin-1 and plasminogen activator inhibitor-1, liver tissue biochemistry, and histopathology were analyzed.
The treatment with FR167653 attenuated microcirculatory disturbance, lessened liver injury, enhanced adenine nucleotides resynthesis, and improved animal survival after liver ischemia. In addition, FR167653 significantly inhibited release of both endothelin-1 and plasminogen activator inhibitor-1 from the liver cells.
These results suggest that the inflammatory cytokines induce microcirculatory disturbance in the initial phase of reperfusion following liver ischemia.
背景/目的：诸如白细胞介素-1β和肿瘤坏死因子-α等炎性细胞因子可激活中性粒细胞，从而导致肝脏热缺血-再灌注损伤。然而，这些细胞因子在再灌注后即刻于肝脏微循环中的作用仍不清楚。本研究旨在探究白细胞介素-1β和肿瘤坏死因子-α的双重抑制剂FR167653是否能减轻肝脏缺血后再灌注初始阶段的肝脏微循环障碍。
成年杂种犬在门体分流下行Pringle手法进行90分钟肝脏缺血。动物被分为两组：对照组（n = 10），仅接受肝脏热缺血；FR167653给药组（n = 5），从缺血前30分钟至再灌注后2小时持续接受1 mg/kg/h的FR167653，共4小时。分析动物7天存活率、肝组织血流量、肝功能检测、肝静脉血中内皮素-1和纤溶酶原激活物抑制剂-1的浓度、肝组织生物化学及组织病理学。
FR167653治疗减轻了微循环障碍，减轻了肝损伤，增强了腺嘌呤核苷酸的再合成，并提高了肝脏缺血后动物的存活率。此外，FR167653显著抑制了肝细胞中内皮素-1和纤溶酶原激活物抑制剂-1的释放。
这些结果表明，炎性细胞因子在肝脏缺血后再灌注的初始阶段诱导了微循环障碍。
