胰蛋白酶原
腺泡细胞
胰腺炎
急性胰腺炎
转基因小鼠
内分泌学
内科学
转基因
胰腺
胰腺疾病
腺泡
胰蛋白酶
蓝绿藻
生物
医学
病理
胆囊收缩素
酶
生物化学
受体
基因
作者
Xi Zhan,Jianhua Wan,Guowei Zhang,Lele Song,Fu Gui,Yuebo Zhang,Yinghua Li,Jia Guo,Rajinder Dawra,Ashok K. Saluja,Ashley N. Haddock,Lizhi Zhang,Yan Bi,Baoan Ji
出处
期刊:American Journal of Physiology-gastrointestinal and Liver Physiology
[American Physiological Society]
日期:2019-06-01
卷期号:316 (6): G816-G825
被引量:26
标识
DOI:10.1152/ajpgi.00004.2019
摘要
Intra-acinar trypsinogen activation occurs in the earliest stages of pancreatitis and is believed to play important roles in pancreatitis pathogenesis. However, the exact role of intra-acinar trypsin activity in pancreatitis remains elusive. Here, we aimed to examine the specific effects of intra-acinar trypsin activity on the development of pancreatitis using a transgenic mouse model. This transgenic mouse model allowed for the conditional expression of a mutant trypsinogen that can be activated specifically inside pancreatic acinar cells. We found that expression of this active mutated trypsin had no significant effect on triggering spontaneous pancreatitis. Instead, several protective compensatory mechanisms, including SPINK1 and heat shock proteins, were upregulated. Notably, these transgenic mice developed much more severe acute pancreatitis, compared with control mice, when challenged with caerulein. Elevated tissue edema, serum amylase, inflammatory cell infiltration and acinar cell apoptosis were dramatically associated with increased trypsin activity. Furthermore, chronic pathological changes were observed in the pancreas of all transgenic mice, including inflammatory cell infiltration, parenchymal atrophy and cell loss, fibrosis, and fatty replacement. These changes were not observed in control mice treated with caerulein. The alterations in pancreata from transgenic mice mimicked the histological changes common to human chronic pancreatitis. Taken together, we provided in vivo evidence that increased intra-acinar activation of trypsinogen plays an important role in the initiation and progression of both acute and chronic pancreatitis. NEW & NOTEWORTHY Trypsinogen is activated early in pancreatitis. However, the roles of trypsin in the development of pancreatitis have not been fully addressed. Using a genetic approach, we showed trypsin activity is critical for the severity of both acute and chronic pancreatitis.
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