Kobayashi Mitsunobu, Takeyoshi Izumi, Yoshinari Daisuke, Matsumoto Koshi, Morishita Yasuo
Second Department of Surgery, Gunma University School of Medicine, Department of Pathology, Nippon Medical School Second Hospital, Kawasaki, Japan.
Surgery. 2002 Mar;131(3):344-9. doi: 10.1067/msy.2002.121097.
Several studies have implicated the mitogen-activated protein kinase (MAPK) signal pathway in non-hepatic organ ischemia-reperfusion injury. However, the role of p38 MAPK in hepatic ischemia-reperfusion injury remains unclear. This study investigated the role of p38 MAPK in hepatic ischemia-reperfusion injury.
Male Sprague-Dawley rats were divided into 4 groups (sham, FR-only, control, and FR-treated groups). The animals in the control and FR-treated groups were subjected to 30 minutes of warm ischemia with congestion of the gut. The FR-only and FR-treated groups received FR167653 (FR), which is a novel p38 MAPK inhibitor. The serum levels of aspartate transaminase, alanine transaminase, lactate dehydrogenase, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) were measured (each, n = 6). Liver tissue blood flow was measured at pre-ischemia, end-ischemia, and 30, 60, 90, and 120 minutes after reperfusion (each, n = 4). The liver tissues in the control and FR-treated groups were excised for p38 MAPK and c-Jun N-terminal kinase (JNK) analyses and histopathology (each, n = 4).
Serum levels of aspartate transaminase, alanine transaminase, lactate dehydrogenase, TNF-alpha, and IL-1beta were significantly lower in the FR-treated group than in the control group, and liver tissue blood flow was significantly higher in the FR-treated group than in the control group. Histopathologically, tissue damage was milder in the FR-treated group than in the control group. Both p38 MAPK and JNK were markedly phosphorylated after 30 minutes of reperfusion, and FR inhibited the phosphorylation of p38 MAPK without affecting the JNK.
FR decreased serum TNF-alpha and IL-1beta levels and liver injury associated with the inhibition of p38 MAPK activation. These results suggest that inhibiting the activation of p38 MAPK may attenuate warm ischemia-reperfusion injury of the liver.
多项研究表明丝裂原活化蛋白激酶（MAPK）信号通路与非肝脏器官的缺血再灌注损伤有关。然而，p38 MAPK在肝脏缺血再灌注损伤中的作用仍不清楚。本研究旨在探讨p38 MAPK在肝脏缺血再灌注损伤中的作用。
将雄性Sprague-Dawley大鼠分为4组（假手术组、仅FR组、对照组和FR处理组）。对照组和FR处理组的动物经历30分钟的温暖缺血并伴有肠道充血。仅FR组和FR处理组给予FR167653（FR），这是一种新型的p38 MAPK抑制剂。测量血清天冬氨酸转氨酶、丙氨酸转氨酶、乳酸脱氢酶、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）水平（每组n = 6）。在缺血前、缺血结束时以及再灌注后30、60、90和120分钟测量肝组织血流量（每组n = 4）。切除对照组和FR处理组的肝脏组织进行p38 MAPK和c-Jun氨基末端激酶（JNK）分析以及组织病理学检查（每组n = 4）。
FR处理组血清天冬氨酸转氨酶、丙氨酸转氨酶、乳酸脱氢酶、TNF-α和IL-1β水平显著低于对照组，且FR处理组肝组织血流量显著高于对照组。组织病理学检查显示，FR处理组的组织损伤比对照组轻。再灌注30分钟后，p38 MAPK和JNK均明显磷酸化，而FR抑制p38 MAPK的磷酸化，对JNK无影响。
FR降低了血清TNF-α和IL-1β水平以及与抑制p38 MAPK活化相关的肝损伤。这些结果表明，抑制p38 MAPK的活化可能减轻肝脏的温暖缺血再灌注损伤。
