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
{"title":"胰蛋白酶缺失的小鼠分泌物诱发的胰腺炎","authors":"Alexandra Demcsák, Siavash Shariatzadeh, Miklós Sahin-Tóth","doi":"10.1152/ajpgi.00310.2023","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>Ctrb1</i> gene (encoding chymotrypsin B1) or the <i>Ctrl</i> gene (encoding chymotrypsin-like protease) disrupted, here we generated the novel <i>Ctrb1-del</i> × <i>Ctrl-KO</i> strain in the C57BL/6N genetic background, which harbors a naturally inactivated <i>Ctrc</i> 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 <i>Ctrb1-del</i> × <i>Ctrl-KO</i> strain exhibited markedly increased intrapancreatic trypsin activation and more severe acute pancreatitis, relative to wild-type C57BL/6N mice. After the acute episode, <i>Ctrb1-del</i> × <i>Ctrl-KO</i> mice spontaneously progressed to chronic pancreatitis, whereas C57BL/6N mice recovered rapidly. The cerulein-induced pancreas pathology in <i>Ctrb1-del</i> × <i>Ctrl-KO</i> mice was highly similar to that previously observed in <i>Ctrb1-del</i> 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.<b>NEW & NOTEWORTHY</b> 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.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G333-G344"},"PeriodicalIF":3.9000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427105/pdf/","citationCount":"0","resultStr":"{\"title\":\"Secretagogue-induced pancreatitis in mice devoid of chymotrypsin.\",\"authors\":\"Alexandra Demcsák, Siavash Shariatzadeh, Miklós Sahin-Tóth\",\"doi\":\"10.1152/ajpgi.00310.2023\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 <i>Ctrb1</i> gene (encoding chymotrypsin B1) or the <i>Ctrl</i> gene (encoding chymotrypsin-like protease) disrupted, here we generated the novel <i>Ctrb1-del</i> × <i>Ctrl-KO</i> strain in the C57BL/6N genetic background, which harbors a naturally inactivated <i>Ctrc</i> 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 <i>Ctrb1-del</i> × <i>Ctrl-KO</i> strain exhibited markedly increased intrapancreatic trypsin activation and more severe acute pancreatitis, relative to wild-type C57BL/6N mice. After the acute episode, <i>Ctrb1-del</i> × <i>Ctrl-KO</i> mice spontaneously progressed to chronic pancreatitis, whereas C57BL/6N mice recovered rapidly. The cerulein-induced pancreas pathology in <i>Ctrb1-del</i> × <i>Ctrl-KO</i> mice was highly similar to that previously observed in <i>Ctrb1-del</i> 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.<b>NEW & NOTEWORTHY</b> 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.</p>\",\"PeriodicalId\":7725,\"journal\":{\"name\":\"American journal of physiology. Gastrointestinal and liver physiology\",\"volume\":\" \",\"pages\":\"G333-G344\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427105/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of physiology. Gastrointestinal and liver physiology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1152/ajpgi.00310.2023\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/9 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Gastrointestinal and liver physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1152/ajpgi.00310.2023","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/9 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
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.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
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.
期刊最新文献
Simultaneous optical imaging of gastric slow waves and contractions in the in vivo porcine stomach. Parenteral nutrition results in peripheral ileal to hepatic circadian discordance in mice. AHCC inhibited hepatic stellate cells activation by regulation of cytoglobin induction via TLR2-SAPK/JNK pathway and collagen production via TLR4-NF-κβ pathway. Formal degree programs in physiology promote careers of clinical scientists and benefit basic science departments. Hepatic bile acid accretion correlates with cholestatic liver injury and therapeutic response in Cyp2c70 knockout mice with a humanized bile acid composition.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1