胰蛋白酶缺失的小鼠分泌物诱发的胰腺炎

IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY American journal of physiology. Gastrointestinal and liver physiology Pub Date : 2024-09-01 Epub Date: 2024-07-09 DOI:10.1152/ajpgi.00310.2023
Alexandra Demcsák, Siavash Shariatzadeh, Miklós Sahin-Tóth
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引用次数: 0

摘要

丝氨酸蛋白酶糜蛋白酶通过降解消化蛋白酶胰蛋白酶的前体--胰蛋白酶原,保护胰腺免受胰腺炎的侵害。利用以前产生的Ctrb1基因(编码糜蛋白酶B1)或Ctrl基因(编码糜蛋白酶样蛋白酶)被破坏的小鼠模型,我们在这里产生了新的Ctrb1-del ×Ctrl-KO品系,该品系是在C57BL/6N遗传背景下产生的,其中含有自然失活的Ctrc基因(编码糜蛋白酶C)。新产生的小鼠体内没有糜蛋白酶,但发育正常,繁殖能力强,没有自发表型,这表明糜蛋白酶在实验室条件下是可有可无的。与野生型 C57BL/6N 小鼠相比,当给予 Ctrb1-del ×Ctrl-KO 株小鼠胰蛋白酶时,其胰腺内胰蛋白酶活化明显增加,并表现出更严重的急性胰腺炎。急性发作后,Ctrb1-del ×Ctrl-KO 小鼠自发发展为慢性胰腺炎,而 C57BL/6N 小鼠则迅速恢复。Ctrb1-del ×Ctrl-KO小鼠的胰蛋白酶诱导的胰腺病理变化与之前在Ctrb1-del小鼠中观察到的病理变化高度相似,但胰蛋白酶活化更强,胰腺炎的严重程度更高。总之,这些结果证实并扩展了之前的观察结果,即糜蛋白酶通过限制病理性胰蛋白酶活性来保护胰腺免受胰腺炎的侵害。在小鼠体内,占糜蛋白酶总含量约 90% 的 CTRB1 异构体主要负责抗胰蛋白酶防御和保护胰腺炎,但次要的 CTRL 异构体也有相当大的贡献。
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Secretagogue-induced pancreatitis in mice devoid of chymotrypsin.

The serine protease chymotrypsin protects the pancreas against pancreatitis by degrading trypsinogen, the precursor to the digestive protease trypsin. Taking advantage of previously generated mouse models with either the Ctrb1 gene (encoding chymotrypsin B1) or the Ctrl gene (encoding chymotrypsin-like protease) disrupted, here we generated the novel Ctrb1-del × Ctrl-KO strain in the C57BL/6N genetic background, which harbors a naturally inactivated Ctrc gene (encoding chymotrypsin C). The newly created mice are devoid of chymotrypsin, yet the animals develop normally, breed well, and show no spontaneous phenotype, indicating that chymotrypsin is dispensable under laboratory conditions. When given cerulein, the Ctrb1-del × Ctrl-KO strain exhibited markedly increased intrapancreatic trypsin activation and more severe acute pancreatitis, relative to wild-type C57BL/6N mice. After the acute episode, Ctrb1-del × Ctrl-KO mice spontaneously progressed to chronic pancreatitis, whereas C57BL/6N mice recovered rapidly. The cerulein-induced pancreas pathology in Ctrb1-del × Ctrl-KO mice was highly similar to that previously observed in Ctrb1-del mice; however, trypsin activation was more robust and pancreatitis severity was increased. Taken together, the results confirm and extend prior observations demonstrating that chymotrypsin safeguards the pancreas against pancreatitis by limiting pathologic trypsin activity. In mice, the CTRB1 isoform, which constitutes about 90% of the total chymotrypsin content, is responsible primarily for the anti-trypsin defenses and protection against pancreatitis; however, the minor isoform CTRL also contributes to an appreciable extent.NEW & NOTEWORTHY Chymotrypsins defend the pancreas against the inflammatory disorder pancreatitis by degrading harmful trypsinogen. This study demonstrates that mice devoid of pancreatic chymotrypsins are phenotypically normal but become sensitized to secretagogue hyperstimulation and exhibit increased intrapancreatic trypsin activation, more severe acute pancreatitis, and rapid progression to chronic pancreatitis. The observations confirm and extend the essential role of chymotrypsins in pancreas health.

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来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
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