Müller Sarah, Kaiser Hannah, Krüger Burkhard, Fitzner Brit, Lange Falko, Bock Cristin N, Nizze Horst, Ibrahim Saleh M, Fuellen Georg, Wolkenhauer Olaf, Jaster Robert
Division of Gastroenterology, Department of Medicine II, University Medicine Rostock, Rostock, Germany.
Division of Medical Biology, University Medicine Rostock, Rostock, Germany.
PLoS One. 2014 Apr 10;9(4):e94494. doi: 10.1371/journal.pone.0094494. eCollection 2014.
Reactive oxygen species (ROS) have been implicated in the pathogenesis of acute pancreatitis (AP) for many years but experimental evidence is still limited. Uncoupling protein 2 (UCP2)-deficient mice are an accepted model of age-related oxidative stress. Here, we have analysed how UCP2 deficiency affects the severity of experimental AP in young and older mice (3 and 12 months old, respectively) triggered by up to 7 injections of the secretagogue cerulein (50 μg/kg body weight) at hourly intervals. Disease severity was assessed at time points from 3 hours to 7 days based on pancreatic histopathology, serum levels of alpha-amylase, intrapancreatic trypsin activation and levels of myeloperoxidase (MPO) in lung and pancreatic tissue. Furthermore, in vitro studies with pancreatic acini were performed. At an age of 3 months, UCP2-/- mice and wild-type (WT) C57BL/6 mice were virtually indistinguishable with respect to disease severity. In contrast, 12 months old UCP2-/- mice developed a more severe pancreatic damage than WT mice at late time points after the induction of AP (24 h and 7 days, respectively), suggesting retarded regeneration. Furthermore, a higher peak level of alpha-amylase activity and gradually increased MPO levels in pancreatic and lung tissue were observed in UCP2-/- mice. Interestingly, intrapancreatic trypsin activities (in vivo studies) and intraacinar trypsin and elastase activation in response to cerulein treatment (in vitro studies) were not enhanced but even diminished in the knockout strain. Finally, UCP2-/- mice displayed a diminished ratio of reduced and oxidized glutathione in serum but no increased ROS levels in pancreatic acini. Together, our data indicate an aggravating effect of UCP2 deficiency on the severity of experimental AP in older but not in young mice. We suggest that increased severity of AP in 12 months old UCP2-/- is caused by an imbalanced inflammatory response but is unrelated to acinar cell functions.
多年来，活性氧（ROS）一直被认为与急性胰腺炎（AP）的发病机制有关，但实验证据仍然有限。解偶联蛋白2（UCP2）缺陷小鼠是公认的与年龄相关的氧化应激模型。在此，我们分析了UCP2缺陷如何影响年轻和老年小鼠（分别为3个月和12个月大）实验性AP的严重程度，该实验性AP由每隔1小时注射多达7次促分泌素雨蛙肽（50μg/kg体重）引发。基于胰腺组织病理学、血清α-淀粉酶水平、胰腺内胰蛋白酶激活以及肺和胰腺组织中髓过氧化物酶（MPO）水平，在3小时至7天的时间点评估疾病严重程度。此外，还进行了胰腺腺泡的体外研究。在3个月大时，UCP2基因敲除小鼠和野生型（WT）C57BL/6小鼠在疾病严重程度方面几乎没有区别。相比之下，在诱导AP后的后期时间点（分别为24小时和7天），12个月大的UCP2基因敲除小鼠比WT小鼠出现了更严重的胰腺损伤，提示再生延迟。此外，在UCP2基因敲除小鼠中观察到α-淀粉酶活性的峰值水平更高，并且胰腺和肺组织中的MPO水平逐渐升高。有趣的是，在基因敲除品系中，胰腺内胰蛋白酶活性（体内研究）以及对雨蛙肽治疗的腺泡内胰蛋白酶和弹性蛋白酶激活（体外研究）并未增强，反而减弱。最后，UCP2基因敲除小鼠血清中还原型和氧化型谷胱甘肽的比例降低，但胰腺腺泡中的ROS水平并未升高。总之，我们的数据表明UCP2缺陷对老年而非年轻小鼠实验性AP的严重程度有加重作用。我们认为，12个月大的UCP2基因敲除小鼠中AP严重程度增加是由炎症反应失衡引起的，但与腺泡细胞功能无关。
