Fu K, Tomita T, Sarras M P, De Lisle R C, Andrews G K
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City 66160-7421, USA.
Pancreas. 1998 Oct;17(3):238-46. doi: 10.1097/00006676-199810000-00003.
Oxidative stress has been proposed to play a role in the early events of acute pancreatitis, and metallothionein (MT) can provide protection against oxidative stress. Using transgenic mice, we characterized the effects of depletion of MT-I and -II, or overexpression of MT-I, on pancreatic responses during cerulein-induced acute pancreatitis. In MT-I/-II knockout mice, repeated injections of cerulein caused (a) higher serum amylase levels at 3 and 7 h after the initiation of acute pancreatitis; (b) earlier and stronger upregulation of oxidative stress-responsive genes, including heme oxygenase (HO)-1 and c-fos; and (c) exacerbated tissue damage (edema and polymorphonuclear neutrophil infiltration) compared with nontransgenic 129/SvCPJ mice. Total pancreatic glutathione (GSH + GSSG) content was similar between the knockout and nontransgenic 129/SvCPJ mice. Interestingly, during acute pancreatitis, CD-1 mice pretreated with L-buthionine-[S,R]-sulfoximine (BSO), which dramatically depleted pancreatic GSH, also had more severe pancreatitis, based on the same three criteria listed above, relative to untreated controls. No effects were observed with BSO treatment alone. Finally, during cerulein-induced acute pancreatitis, MT-I overexpressing transgenic mice (>20-fold increase in pancreatic MT-I content) had lower serum alpha-amylase levels between 7 and 24 h and delayed upregulation of HO-1 mRNA levels, but no difference in c-fos mRNA induction relative to the appropriate strain of nontransgenic mice. Diminished tissue damage (particularly cellular necrosis) was noted in these MT-I overexpressing transgenic mice. Total pancreatic GSH content was similar in these transgenic and nontransgenic mice during cerulein-induced acute pancreatitis. These studies suggest that pancreatic MT can function as an intracellular antioxidant as does GSH and that these intracellular antioxidants play a protective role during cerulein-induced acute pancreatitis.
氧化应激被认为在急性胰腺炎的早期事件中起作用，而金属硫蛋白（MT）可以提供抗氧化应激的保护作用。我们使用转基因小鼠，研究了MT-I和-II缺失或MT-I过表达对雨蛙肽诱导的急性胰腺炎期间胰腺反应的影响。在MT-I/-II基因敲除小鼠中，重复注射雨蛙肽导致：（a）急性胰腺炎开始后3小时和7小时血清淀粉酶水平升高；（b）氧化应激反应基因，包括血红素加氧酶（HO）-1和c-fos，更早且更强地上调；（c）与非转基因129/SvCPJ小鼠相比，组织损伤（水肿和多形核中性粒细胞浸润）加剧。基因敲除小鼠和非转基因129/SvCPJ小鼠的胰腺总谷胱甘肽（GSH + GSSG）含量相似。有趣的是，在急性胰腺炎期间，用L-丁硫氨酸-[S,R]-亚砜亚胺（BSO）预处理的CD-1小鼠，其胰腺GSH显著耗尽，基于上述相同的三个标准，相对于未处理的对照组，胰腺炎也更严重。单独使用BSO处理未观察到效果。最后，在雨蛙肽诱导的急性胰腺炎期间，MT-I过表达的转基因小鼠（胰腺MT-I含量增加20倍以上）在7至24小时之间血清α-淀粉酶水平较低，HO-1 mRNA水平上调延迟，但与相应品系的非转基因小鼠相比，c-fos mRNA诱导没有差异。在这些MT-I过表达的转基因小鼠中，组织损伤（特别是细胞坏死）减轻。在雨蛙肽诱导的急性胰腺炎期间，这些转基因小鼠和非转基因小鼠的胰腺总GSH含量相似。这些研究表明，胰腺MT可以像GSH一样作为细胞内抗氧化剂发挥作用，并且这些细胞内抗氧化剂在雨蛙肽诱导的急性胰腺炎期间起保护作用。
