Murayama Takaya, Tanabe Minoru, Matsuda Satoshi, Shimazu Motohide, Kamei Shusaku, Wakabayashi Go, Kawachi Shigeyuki, Matsumoto Kenji, Yamazaki Kazuto, Matsumoto Koshi, Koyasu Shigeo, Kitajima Masaki
Department of Surgery, Keio University School of Medicine, and Department of Pathology, Saiseikai Central Hospital, Tokyo, Japan.
Transplantation. 2006 May 15;81(9):1325-30. doi: 10.1097/01.tp.0000209167.48030.6b.
In small intestinal ischemia reperfusion injury, we investigated the pathophysiological role of c-Jun NH2 terminal kinase (JNK) and p38 in order to determine whether the dual inhibition of JNK and p38 was beneficial.
Ischemia reperfusion injury was induced by clamping the superior mesenteric artery for 30 min in Wistar male rats. The inhibition of JNK and p38 was achieved with LL-Z1640-2 as a novel JNK and p38 dual inhibitor in vivo. Between the non-treatment group (Control group) and the LL-Z1640-2 treatment group (LL-Z group), the following findings were compared; histological damage by hematoxylin and eosin (H. E.) staining, JNK and p38 activation by a kinase assay, the localization of apoptosis using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, the localization of activated JNK and activated p38 based on immunohistochemistry.
The activation of JNK and p38 increased remarkably after reperfusion according to a kinase assay. In immunohistochemistry for activated JNK and activated p38, a remarkable degree of positive staining was revealed in the nucleus of the detached epithelial cells from the tip of villi after reperfusion. In addition, many TUNEL positive cells were observed in the detached epithelial cells where JNK and p38 were activated. Pretreatment of LL-Z1640-2 inhibited the activation of JNK and p38, and also significantly improved the histological damage.
These results suggest that JNK and p38 both play a key role during small intestinal ischemia reperfusion injury through a proapoptotic action on the tip of villi.
在小肠缺血再灌注损伤中，我们研究了c-Jun氨基末端激酶（JNK）和p38的病理生理作用，以确定对JNK和p38的双重抑制是否有益。
通过夹闭Wistar雄性大鼠肠系膜上动脉30分钟诱导缺血再灌注损伤。在体内使用新型JNK和p38双重抑制剂LL-Z1640-2抑制JNK和p38。在非治疗组（对照组）和LL-Z1640-2治疗组（LL-Z组）之间，比较了以下结果；苏木精和伊红（H.E.）染色显示的组织学损伤、激酶测定显示的JNK和p38激活、使用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）方法进行的细胞凋亡定位、基于免疫组织化学的活化JNK和活化p38的定位。
根据激酶测定，再灌注后JNK和p38的激活显著增加。在活化JNK和活化p38的免疫组织化学中，再灌注后绒毛尖端脱离的上皮细胞核中显示出显著程度的阳性染色。此外，在JNK和p38被激活的脱离上皮细胞中观察到许多TUNEL阳性细胞。LL-Z1640-2预处理抑制了JNK和p38的激活，并且还显著改善了组织学损伤。
这些结果表明，JNK和p38在小肠缺血再灌注损伤过程中均通过对绒毛尖端的促凋亡作用发挥关键作用。
