Division of Basic and Translational Research, Department of Surgery, University of Minnesota Medical School, Minneapolis, MN, USA.
Gastroenterology. 2013 May;144(5):1076-1085.e2. doi: 10.1053/j.gastro.2013.01.041. Epub 2013 Jan 24.
BACKGROUND & AIMS: Premature activation of trypsinogen activation can cause pancreatic injury and has been associated with chronic pancreatitis (CP). Mice that lack intra-acinar activation of trypsinogen, such as trypsinogen-7-null (T(-/-)) and cathepsin B-null (CB(-/-)) mice, have been used to study trypsin-independent processes of CP development. We compared histologic features and inflammatory responses of pancreatic tissues from these mice with those from wild-type mice after the development of CP.
CP was induced in wild-type, T(-/-), and CB(-/-) mice by twice-weekly induction of acute pancreatitis for 10 weeks; acute pancreatitis was induced by hourly intraperitoneal injections of cerulein (50 μg/kg × 6). Pancreatic samples were collected and evaluated by histologic and immunohistochemical analyses. Normal human pancreas samples, obtained from the islet transplant program at the University of Minnesota, were used as controls and CP samples were obtained from surgical resections.
Compared with pancreatic tissues from wild-type mice, those from T(-/-) and CB(-/-) mice had similar levels of atrophy, histomorphologic features of CP, and chronic inflammation. All samples had comparable intra-acinar activation of nuclear factor (NF)-κB, a transcription factor that regulates the inflammatory response, immediately after injection of cerulein. Pancreatic tissue samples from patients with CP had increased activation of NF-κB (based on nuclear translocation of p65 in acinar cells) compared with controls.
Induction of CP in mice by cerulein injection does not require intra-acinar activation of trypsinogen. Pancreatic acinar cells of patients with CP have increased levels of NF-κB activation compared with controls; regulation of the inflammatory response by this transcription factor might be involved in the pathogenesis of CP.
胰蛋白酶原过早激活可导致胰腺损伤，并与慢性胰腺炎（CP）有关。缺乏胰蛋白酶原在腺泡内激活的小鼠，如胰蛋白酶原-7 缺失（T（-/-））和组织蛋白酶 B 缺失（CB（-/-））小鼠，已被用于研究 CP 发展中胰蛋白酶非依赖性过程。我们比较了这些小鼠与野生型小鼠在 CP 发展后的胰腺组织的组织学特征和炎症反应。
通过每周两次诱导急性胰腺炎 10 周，在野生型、T（-/-）和 CB（-/-）小鼠中诱导 CP；急性胰腺炎通过每小时腹腔内注射 Cerulein（50μg/kg×6）诱导。收集胰腺样本，通过组织学和免疫组织化学分析进行评估。正常的人类胰腺样本取自明尼苏达大学胰岛移植项目，作为对照，CP 样本取自手术切除。
与野生型小鼠的胰腺组织相比，T（-/-）和 CB（-/-）小鼠的胰腺组织萎缩程度、CP 的组织形态学特征和慢性炎症相似。在注射 Cerulein 后立即，所有样本的核因子（NF）-κB（调节炎症反应的转录因子）的腺泡内激活水平相当。与对照组相比，CP 患者的胰腺组织样本中 NF-κB 的激活水平增加（基于腺泡细胞中 p65 的核转位）。
通过 Cerulein 注射诱导小鼠 CP 不需要胰蛋白酶原在腺泡内的激活。与对照组相比，CP 患者的胰腺腺泡细胞中 NF-κB 的激活水平增加；该转录因子对炎症反应的调节可能参与 CP 的发病机制。
