Hartwig W, Jimenez R E, Werner J, Lewandrowski K B, Warshaw A L, Fernández-del Castillo C
Department of Surgery, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
Gastroenterology. 1999 Sep;117(3):717-25. doi: 10.1016/s0016-5085(99)70466-x.
BACKGROUND & AIMS: Intracellular activation of trypsinogen is currently believed to initiate pancreatitis. Factors responsible for the progression of mild to necrotizing pancreatitis are poorly understood. This study evaluated the significance of interstitial protease release and activation in this process.
In rats with cerulein-induced pancreatitis, concentrations of trypsinogen and its activation peptide TAP were measured in lymph and blood, and pancreatic injury was determined. Activation of extracellular trypsinogen was induced by intravenous infusion of enterokinase, which does not enter the acinar cell. Gabexate mesilate (acinar cell permeable) or soybean trypsin inhibitor (acinar cell nonpermeable) was administered to distinguish the effects of intracellular or extracellular protease activation.
In cerulein pancreatitis, trypsinogen levels increased prominently and were highest in lymph and portal vein blood, whereas TAP increments were modest. Combined cerulein/enterokinase infusions resulted in marked TAP increases in lymph and blood and in severe necrohemorrhagic pancreatitis. Gabexate mesilate as well as soybean trypsin inhibitor significantly decreased TAP levels in both lymph and blood and reduced pancreatic injury, with no significant differences between groups.
In secretagogue-induced pancreatitis, large amounts of trypsinogen are present in the interstitium and drain via the portal and lymphatic circulation. Activation of this extracellular trypsinogen induces hemorrhagic necrosis in a setting of mild edematous pancreatitis. This phenomenon may be the central event in the progression to fulminant necrotizing pancreatitis.
目前认为胰蛋白酶原的细胞内激活会引发胰腺炎。对于轻症胰腺炎发展为坏死性胰腺炎的相关因素，人们了解甚少。本研究评估了间质蛋白酶释放和激活在此过程中的意义。
在经雨蛙肽诱导胰腺炎的大鼠中，检测淋巴液和血液中胰蛋白酶原及其激活肽TAP的浓度，并确定胰腺损伤情况。通过静脉输注不进入腺泡细胞的肠激酶来诱导细胞外胰蛋白酶原的激活。给予甲磺酸加贝酯（可透过腺泡细胞）或大豆胰蛋白酶抑制剂（不可透过腺泡细胞）以区分细胞内或细胞外蛋白酶激活的作用。
在雨蛙肽诱导的胰腺炎中，胰蛋白酶原水平显著升高，在淋巴液和门静脉血中最高，而TAP的升高幅度较小。联合输注雨蛙肽/肠激酶导致淋巴液和血液中TAP显著增加，并引发严重的坏死性出血性胰腺炎。甲磺酸加贝酯以及大豆胰蛋白酶抑制剂均显著降低了淋巴液和血液中的TAP水平，并减轻了胰腺损伤，两组之间无显著差异。
在促分泌素诱导的胰腺炎中，大量胰蛋白酶原存在于间质中，并通过门静脉和淋巴循环引流。这种细胞外胰蛋白酶原的激活在轻度水肿性胰腺炎的情况下会诱发出血性坏死。这一现象可能是发展为暴发性坏死性胰腺炎的核心事件。
