Pathophysiological role of CCK in acute experimental pancreatitis

在精氨酸诱导的急性胰腺炎大鼠14天内，用抗pcna或抗br dU抗体免疫金银染色法估计腺泡细胞再生情况。PCNA标记指数（L.I.），以1000个腺泡细胞中PCNA阳性细胞的百分比表示，在第0.5天和第7天出现两个高峰，血浆CCK生物活性在急性胰腺炎发病后迅速增加，在第3天达到高峰，然后在第11天保持高水平。急性胰腺炎再生期血浆CCK水平升高与Br dU l i显著相关。此外，长期服用CCK受体拮抗剂CR1505，不仅明显抑制了急性胰腺炎后正常的胰腺生长，还抑制了腺泡再生。基于这些数据，我们得出结论，内源性CCK在急性胰腺炎的腺泡细胞增殖中起重要作用。我们还通过亚细胞分离的方法研究了CCK在急性胰腺炎细胞内发病机制中的作用。在细小蛋白和精氨酸诱导的胰腺炎中，我们发现组织蛋白酶B重新分布到酶原部分。随后胰蛋白酶原对胰蛋白酶的激活在精氨酸型胰腺炎中被确认，但在小蛋白型胰腺炎中未被确认。CR1505对两种模型中组织蛋白酶B的再分布均有轻微改善。CR1505对小蛋白性胰腺炎有保护作用，对精氨酸性胰腺炎无保护作用。本研究明确了CCK在急性胰腺炎病理生理中的作用，但我们需要进一步研究急性胰腺炎中腺泡细胞内的事件。

During 14 days in rats with arginine-induced acute pancreatitis, acinar cell regener ation was estimated by using immunogold-silver staining with anti-PCNA or anti-Br dU antibody. PCNA labeling index (L.I.), that was expressed as percentage of PCNA positive cells in 1000 acinar cells, indicated two major peaks on day 0.5 and 7 as well as Br dU L.I.Plasma CCK bioactivities which increased rapidly following the onset of acute pancreatitis reached the peak on day 3, and then continued high levels during 11 days. Increased levels of plasma CCK significantly correlated with Br dU L.I.during regenerative phase of acute pancreatitis. Furthermore, long-term administration of CR1505, a CCK receptor antagonist, apparently suppressed not only normal pancreatic growth but also acinar regeneration following acute pancreatitis. Based in these data, it is concluded that endogenous CCK plays an important role in acinar cell proliferation even in acute pancreatitis. We investigated also an role of CCK in intracellular pathogenesis of acute pancreatitis by using the method of the subcellular fractionation. In both caerulein- and arginine-induced pancreatitis, we found the redistribution of cathepsin B into zymogen fraction. Subsequent activation of trypsinogen to trypsin was recognized in arginine-pancreatitis but not in caerulein-pancreatitis. CR1505 caused minor improvement of the redistribution of cathepsin B in both model. Protective effect of CR1505 on acute pancreatitis was obtained in caerulein-pancreatitis and not in arginine-pancreatitis. The role of CCK on the pathophysiology of acute pancreatitis was clarified in the present study but we should study further the intracellular events in acinar cells in acutepancreatitis.