Van Acker Gijs J D, Weiss Eric, Steer Michael L, Perides George
Dept. of Surgery, Tufts-New England Medical Center, 860 Washington St., Boston, MA 02111, USA.
Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1738-46. doi: 10.1152/ajpgi.00543.2006. Epub 2007 Mar 1.
We have hypothesized that the colocalization of digestive zymogens with lysosomal hydrolases, which occurs during the early stages of every experimental pancreatitis model, facilitates activation of those zymogens by lysosomal hydrolases such as cathepsin B and that this activation triggers acute pancreatitis by leading to acinar cell injury. Some, however, have argued that the colocalization phenomenon may be the result, rather than the cause, of zymogen activation during pancreatitis. To resolve this controversy and explore the causal relationships between zymogen activation and other early pancreatitis events, we induced pancreatitis in mice by repeated supramaximal secretagogue stimulation with caerulein. Some animals were pretreated with the cathepsin B inhibitor CA-074 me to inhibit cathepsin B, prevent intrapancreatic activation of digestive zymogens, and reduce the severity of pancreatitis. We show that inhibition of cathepsin B by pretreatment with CA-074 me prevents intrapancreatic zymogen activation and reduces organellar fragility, but it does not alter the caerulein-induced colocalization phenomenon or subcellular F-actin redistribution or prevent caerulein-induced activation of NF-kappaB, ERK1/2, and JNK or upregulated expression of cytochemokines. We conclude 1) that the colocalization phenomenon, F-actin redistribution, activation of proinflammatory transcription factors, and upregulated expression of cytochemokines are not the results of zymogen activation, and 2) that these early events in pancreatitis are not dependent on cathepsin B activity. In contrast, zymogen activation and increased subcellular organellar fragility during caerulein-induced pancreatitis are dependent on cathepsin B activity.
我们曾提出假说，即在每种实验性胰腺炎模型的早期阶段出现的消化酶原与溶酶体水解酶的共定位，会促进诸如组织蛋白酶B等溶酶体水解酶对这些酶原的激活，并且这种激活通过导致腺泡细胞损伤而引发急性胰腺炎。然而，一些人认为这种共定位现象可能是胰腺炎期间酶原激活的结果，而非原因。为了解决这一争议并探究酶原激活与其他早期胰腺炎事件之间的因果关系，我们通过用蛙皮素反复进行超最大剂量促分泌素刺激来诱导小鼠发生胰腺炎。一些动物用组织蛋白酶B抑制剂CA-074 me进行预处理，以抑制组织蛋白酶B、防止胰腺内消化酶原的激活并减轻胰腺炎的严重程度。我们发现，用CA-074 me预处理抑制组织蛋白酶B可防止胰腺内酶原激活并降低细胞器的脆弱性，但它不会改变蛙皮素诱导的共定位现象或亚细胞F-肌动蛋白重新分布，也不能防止蛙皮素诱导的核因子κB、细胞外信号调节激酶1/2和应激活化蛋白激酶的激活或细胞趋化因子表达上调。我们得出以下结论：1）共定位现象、F-肌动蛋白重新分布、促炎转录因子的激活以及细胞趋化因子表达上调不是酶原激活的结果；2）胰腺炎中的这些早期事件不依赖于组织蛋白酶B的活性。相比之下，蛙皮素诱导的胰腺炎期间的酶原激活和亚细胞细胞器脆弱性增加依赖于组织蛋白酶B的活性。
