Wagner A C, Mazzucchelli L, Miller M, Camoratto A M, Göke B
Department of Gastroenterology, University of Bern, CH-3010 Bern, Switzerland.
Am J Physiol Gastrointest Liver Physiol. 2000 Jan;278(1):G165-72. doi: 10.1152/ajpgi.2000.278.1.G165.
Pancreatic caerulein-induced activation of c-Jun NH(2)-terminal kinase (JNK) has been reported, and JNK has been proposed as a mediator during induction of hyperstimulated pancreatitis. CEP-1347 has recently been described as a specific JNK inhibitor. We tested whether CEP-1347 inhibits caerulein-induced pancreatic JNK activation in isolated acini and in vivo. CEP-1347 dose dependently inhibited acinar caerulein-induced JNK activation with nearly complete inhibition at 2 microM but had no effect on digestive enzyme release. For in vivo studies, rats were pretreated with CEP-1347 before caerulein hyperstimulation. For assessment of JNK activation and histological alterations, animals were killed 30 min or 2 and 4 h after caerulein hyperstimulation, respectively. Pancreatic wet weight, serum enzyme levels, and pancreatic activity of p38 and extracellular signal-regulated kinase (ERK) were also determined. Caerulein hyperstimulation strongly activated JNK, p38, and ERK. CEP-1347 pretreatment dose dependently reduced caerulein-induced pancreatic JNK activation without p38 or ERK inhibition. JNK inhibition also reduced pancreatic edema formation and reduced histological severity of pancreatitis. Thus we show that CEP-1347 inhibits JNK activation in vivo and ameliorates caerulein-induced pancreatitis.
已有报道称，蛙皮素可诱导胰腺中c-Jun氨基末端激酶（JNK）激活，且JNK被认为是过度刺激型胰腺炎诱导过程中的一种介质。CEP-1347最近被描述为一种特异性JNK抑制剂。我们测试了CEP-1347是否能在离体腺泡及体内抑制蛙皮素诱导的胰腺JNK激活。CEP-1347能剂量依赖性地抑制腺泡蛙皮素诱导的JNK激活，在2 microM时几乎完全抑制，但对消化酶释放无影响。对于体内研究，在蛙皮素过度刺激前用CEP-1347预处理大鼠。为评估JNK激活及组织学改变，分别在蛙皮素过度刺激后30分钟、2小时和4小时处死动物。还测定了胰腺湿重、血清酶水平以及p38和细胞外信号调节激酶（ERK）的胰腺活性。蛙皮素过度刺激强烈激活了JNK、p38和ERK。CEP-1347预处理能剂量依赖性地降低蛙皮素诱导的胰腺JNK激活，而不抑制p38或ERK。抑制JNK还能减轻胰腺水肿形成，并降低胰腺炎的组织学严重程度。因此，我们表明CEP-1347能在体内抑制JNK激活，并改善蛙皮素诱导的胰腺炎。
