Jaffray C, Yang J, Norman J
Department of Surgery, University of South Florida, Tampa, Florida 33601, USA.
J Surg Res. 2000 May 15;90(2):95-101. doi: 10.1006/jsre.2000.5832.
Recent evidence suggests that pancreatitis-associated hepatic injury is regulated by inflammatory mediator production. Our laboratory demonstrated in vitro that pancreatic elastase is a pancreatic enzyme that can induce inflammatory cell cytokine production. Therefore we now explore the in vivo effects of elastase on the liver.
Elastase (1.5 U) +/- CNI-1493, which attenuates mediator production through p38 MAP kinase inhibition, was administered intraperitoneally to mice while control animals received saline. Acute pancreatitis (AP) was induced with a choline-deficient, ethionine-supplemented (CDE) diet. Serum hepatic enzymes and hepatic neutrophil infiltration by myeloperoxidase (MPO) activity were measured as indicators of hepatic insult. Serum tumor necrosis factor (TNF) protein (ELISA), hepatic TNF mRNA (reverse transcription polymerase chain reaction), and hepatic activation of the transcription factor nuclear factor kappa B (electrophoretic mobility shift assay) were also determined.
A significant increase in hepatic enzymes and MPO activity was induced by AP and mirrored by intraperitoneal elastase. Both types of liver injury resulted in near identical elevations in serum TNF protein and hepatic TNF mRNA. Elastase-treated animals with mediator production inhibited (CNI-1493) had attenuated hepatic enzymes, MPO activity, TNF protein, and TNF mRNA. Activation of nuclear factor kappa B occurred 30 min after elastase administration.
Exposure of the liver to pancreatic elastase results in hepatic inflammation and injury which appears identical to that seen during severe AP. Prevention of inflammatory mediator production by intrahepatic leukocytes attenuates injury and supports recent adult respiratory distress syndrome and in vitro data suggesting that elastase is the principal factor that propagates pancreatic inflammation into a systemic illness through direct activation of systemic inflammatory cells.
最近的证据表明，胰腺炎相关的肝损伤受炎症介质产生的调节。我们实验室在体外证明，胰腺弹性蛋白酶是一种可诱导炎症细胞细胞因子产生的胰腺酶。因此，我们现在探讨弹性蛋白酶对肝脏的体内作用。
向小鼠腹腔注射弹性蛋白酶（1.5 U）±CNI-1493（通过抑制p38丝裂原活化蛋白激酶来减弱介质产生），而对照动物接受生理盐水。用胆碱缺乏、蛋氨酸补充（CDE）饮食诱导急性胰腺炎（AP）。测量血清肝酶和通过髓过氧化物酶（MPO）活性评估的肝脏中性粒细胞浸润，作为肝损伤的指标。还测定了血清肿瘤坏死因子（TNF）蛋白（酶联免疫吸附测定）、肝脏TNF mRNA（逆转录聚合酶链反应）以及转录因子核因子κB的肝脏活化（电泳迁移率变动分析）。
AP诱导肝酶和MPO活性显著增加，腹腔注射弹性蛋白酶也出现类似情况。两种类型的肝损伤均导致血清TNF蛋白和肝脏TNF mRNA几乎相同程度的升高。介质产生受到抑制（CNI-1493）的弹性蛋白酶处理动物，其肝酶、MPO活性、TNF蛋白和TNF mRNA均有所减轻。给予弹性蛋白酶30分钟后，核因子κB发生活化。
肝脏暴露于胰腺弹性蛋白酶会导致肝脏炎症和损伤，这与严重AP时所见的情况相似。肝内白细胞产生炎症介质的过程受到抑制可减轻损伤，这支持了最近关于成人呼吸窘迫综合征的研究以及体外数据，表明弹性蛋白酶是通过直接激活全身炎症细胞将胰腺炎症传播为全身性疾病的主要因素。
