Development of secretin-loaded breath test as a pancreatic exocrine function test : from animal model to human chronic pancreatitis

作为胰腺外分泌功能测试的促胰液素呼气试验的发展：从动物模型到人类慢性胰腺炎

• 批准号: 14570492
• 负责人: YAMADA Tamaki
• 金额: $ 2.11万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570492/
• 关键词: breath test; chronic pancreatitis; renin angiotensin system; angiotensin-converting enzyme inhibitor; angiotensin II type 1 receptor antagonist; Angiotensin; Renin angiotensin system; Angiotensin II受容体抗体薬

We purposed to develop the secretin-loaded breath test to assess pancreatic exocrine function test using chronic pancreatitis in male WBN/Kob rats. Using Ubit-IR300,we could measure the ratio of ^<12>CO/^<13>CO from the expiration of rats which were put into the sealed container. At the beginning, we put conscious rats into the sealed container to collect their expiration. We thought that keeping rats in the sealed container caused tremendous stress, including hypo O_2 and hyper CO_2. The followings were our methodological modifications:1)Mixed gas (N_2 80%, O_2 20%) is pumped into the sealed container at a constant flow rate to remove pre-existing CO_2 from the collected air.2)Concentrations of O_2 and CO_2 in the air of the sealed container were monitored to keep O_2 and CO_2 around 20% and below 1%, respectively.3)The exhaust was placed on the lid of the container to remove excess N_2 and O_2.4)The expiration CO_2 with high density was collected from the bottom of the container.We r … More ecognized that the ratios of ^<12>CO/^<13>CO were not significantly lower in 20 and 30 weeks old male WBN/Kob rats than the age-matched male Wistar rats. Since it is reported that pancreatic exocrine function is impaired in 20 and 30 weeks old male WBN/Kob rats, the present breath test has low sensitivity.At the same time, we treated 10 weeks old male WBN/Kob rats with lisinopril, angiotensin-converting enzyme (ACE) inhibitor, in drinking water for 10 weeks and found that lisinopril dramatically attenuated pancreatic inflammation and fibrosis at 20 weeks of age by suppressing transforming growth factor-β1 mRNA. Therefore, we shifted the direction of the experiment and newly aimed to explore the roles of renin-angiotensin system (RAS) in the pathogenesis of chronic pancreatitis in the present model. As a result, both lisinopril, ACE inhibitor, and candesartan, angiotensin II type 1 receptor antagonist (ARB) effectively attenuated pancreatic inflammation and fibrosis in the present model (Gastroenterology 124:1010-1019,2003,J Pharmacol Exp Ther J Pharmacol Exp Ther 307:17-23,2003), demonstrating the important roles of RAS in the pathogenesis of chronic pancreatitis. However, their doses were extremely higher than the clinically used doses. Therefore, we next assessed the effect of combined therapy with ACE inhibitor and ARB. We finally found that combined therapy with ineffective doses of ACE inhibitor and ARB attenuated pancreatic inflammation and fibrosis in the present model. Less

本研究旨在建立分泌素负荷呼气试验，以慢性胰腺炎大鼠为模型，评价胰腺外分泌功能。用Ubit-IR 300测定密闭容器中大鼠呼气中的^<12>CO/^<13>CO比值。首先，我们将清醒的大鼠放入密封容器中收集其呼气。我们认为把大鼠关在密封容器中会造成巨大的压力，包括低氧和高二氧化碳。方法学上的改进是：（1）在密闭容器中以恒定流量泵入混合气体（N_280%，O_220%），以去除空气中预先存在的CO_2。（2）监测密闭容器中O_2和CO_2的浓度，使O_2和CO_2分别保持在20%和1%以下。（3）在容器盖上放置排气装置，以去除过量的N_2和O_2。（4）从容器底部收集高浓度的呼出CO_2。我们对实验结果进行了分析。 ...更多信息 20<12><13>周龄和30周龄雄性WBN/Kob大鼠的^ CO/^ CO比值并不显著低于同龄雄性Wistar大鼠。由于20周龄和30周龄雄性WBN/Kob大鼠胰腺外分泌功能受损，目前的呼气试验敏感性较低，同时，我们用赖诺普利、血管紧张素转换酶（ACE）抑制剂、发现赖诺普利在20周龄时通过抑制转化生长显著减轻胰腺炎症和纤维化β1因子mRNA。因此，我们改变了实验方向，在本模型中探讨了肾素-血管紧张素系统（RAS）在慢性胰腺炎发病机制中的作用。结果，赖诺普利（ACE抑制剂）和坎地沙坦（血管紧张素II 1型受体拮抗剂（ARB））都有效地减轻了本模型中的胰腺炎症和纤维化（Gastroenterology 124：1010-1019，2003，J Pharmacol Exp Ther J Pharmacol Exp Ther 307：17- 23，2003），证明了RAS在慢性胰腺炎发病机制中的重要作用。然而，它们的剂量远远高于临床使用的剂量。因此，我们接下来评估了ACE抑制剂和ARB联合治疗的效果。我们最终发现，无效剂量的ACE抑制剂和ARB的联合治疗减轻了本模型中的胰腺炎症和纤维化。少

项目成果

Atsushi Kuno, Tamaki Y Kazuhiko Mnsuda, et al.: "Angiotensin-conveiling enzyme inhibitor attenuates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats."Gastroenterology. 124. 1010-1019 (2003)

Atsushi Kuno、Tamaki Y Kazuhiko Mnsuda 等人：“血管紧张素转导酶抑制剂可减轻雄性 Wistar Bonn/Kobori 大鼠的胰腺炎症和纤维化。”胃肠病学。

A.Kuno, T.Yamada, et al.: "Angiotensin-Converting Enzyme Inhibitor Attenuates Pancreatic Inflammation and Fibrosis in Male Wistar Bonn/Kobori Rats"Gastroenterology. 124・4(in press). (2003)

A.Kuno、T.Yamada 等人：“血管紧张素转换酶抑制剂减轻雄性 Wistar Bonn/Kobori 大鼠的胰腺炎症和纤维化”胃肠病学 124・4（印刷中）。

Tamaki Yamada, Atsushi Kuno, Kazuhiko Masuda, et al.: "Candesartan, an angiotensin II receptor antagonist, suppresses pancreatic inflammation and fibrosis in rats."J Pharmacol Exp Ther. 307. 17-23 (2003)

Tamaki Yamada、Atsushi Kuno、Kazuhiko Masuda 等人：“坎地沙坦是一种血管紧张素 II 受体拮抗剂，可抑制大鼠的胰腺炎症和纤维化。”J Pharmacol Exp Ther。

Atsushi Kuno, Tamaki Yamada, Kazuhiko Masuda, et al.: "Angiotensin-converting enzyme inhibitor attenuates pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori rats."Gastroenterology. 124. 1010-1019 (2003)

Atsushi Kuno、Tamaki Yamada、Kazuhiko Masuda 等人：“血管紧张素转换酶抑制剂可减轻雄性 Wistar Bonn/Kobori 大鼠的胰腺炎症和纤维化。”胃肠病学。