Studies on Prostaglandins in the Pancreas

胰腺中前列腺素的研究

• 批准号: 01570398
• 负责人: HARADA Hideo
• 金额: $ 1.54万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01570398/
• 关键词: Pancreatitis; Caerulein Pancreatitis; Prostaglandins; Thromboxane; Pancreatic Juice; Therapy; Indomethacin; 膵臓; 膵炎の経過; 純粋膵液; プロスタグランディンE_2; トロンボキサンB_2; プロスタグランディンI_2; 慢性膵炎; アラキドン酸; 飲酒; アルコ-ル; 加齢

We have demonstrated that the levels of prostaglandins(PGs)and thromboxane(TX)are elevated in pure pancreatic juice from patients with pancreatitis. The findings led us to investigate the role of PGs and TX in the pathophysiology and treatment of pancreatitis.1. Basic investigations :Preliminary studies showed that caerulein-induced pancreatitis in rats is most suitable for the study and that caerulein(Cn)(Sigma, St. Louis, USA)10 ug/kg should be injected subcutaneously four times at 1-hour intervals to be sacrificed at 6 hours for quantitating pancreas weight, ascites, serum pancreatic enzymes, and histologic evidence of damage. In the second experiment, effects of 16, 16-dimethyl PGE2(dmPGE2)or indomethacin(IND)on pancreatitis were determined. dmPGE2(10, 30 or 100 ug/kg)was injected subcutaneously twice(30 min before and 3 hours after the start of Cn injection), once 30 min before, or once 30 min after the start of Cn injection. Indomethacin(IND)(Sigma, St. Louis, USA)5 mg/kg was inj … More ected subcutaneously 1 hour before and 3 hours after the start of Cn injection. In the third experiment, effects of dmPGE2 or IND on pancreatic content of endogenous PGs and TXB2 were evaluated. Based on a preliminary study. Cn 10 ug/kg was injected twice and rats were killed at 2 hours. dmPGE2 100 ug/kg or IND 5 mg/kg was injected 30 min before the start of Cn-injection. The Cn dosage induced edematous pancreatitis(edema, vacuoles, cell infiltration)without necrosis. dmPGE2 induced dose- and time-dependent improvements in the severity of pancreatitis. A combination of pre- and post-treatment with dmPGE2 induced a marked improvement, whereas either pre- or post-treatment alone induced only a mild improvement. In contrast, IND exerted deleterious effects on the above parameters with appearance of pancreatic necrosis. Cn-induced pancreatitis showed a marked increase in endogenous PGE2, 6-koto-PGF1a, TXB2 and 6-keto-PGF1a/TXB2 ratio. IND and dmPGE2 administration induced a marked decrease in PGE2.6-keto-PGF1a, TXB2, 6-keto-PGF1a/TXB2 ratio and PGE2/TXB2 ratio. In dmPGE2-treated rats, the decrease of endogenous PGE2 was wellcompensated for by exogenous dmPGE2 ; however, the decreased 6-keto-PGF1a/TXB2 ratio was considered to carry a potential risk of deteriorating pancreatitis, depending on pancreatitis models. In IND-treated rats, in contrast, the decreased 6-keto-PGF1a and 6-keto-PGF1a/TXB2 ratio was considered to induce deterioration with pancreatic necrosis in the setting of decreased PGE2 and PGE2/TXB2 ratio.2. Clinical studies :Characteristic findings in pure pancreatic juice from patients with pancreatitis were raised levels of TXB2 and TXB2/6-keto-PGF1a ratio on clinical exacerbations and restorations towards normal on clinical improvements. Indomethacin at doses given in clinical practice induced neither clinical exacerbations nor significant decreases in PGE2/TXB2 ratio and 6-keto-PGF1a/TXB2 ratio.In conclusion, PGE2 gives a protective effect on pancreatitis in rats. However, clinical use of exogenous PGE2 for the therapy of pancreatitis is not presently justified because of insufficient efficacy of PGE2 given after the onset of pancreatitis and a potential risk of a decreased 6-keto-PGF1a/TXB2 ratio. Indomethacin frequently used for pain relief should be prescribed cautiously because of a potential risk of deteriorating pancreatitis through a decrease in endogenous 6keto-PGF1a, 6-keto-PGF1a/TXB2 ratio. PGE2. and PGE2/TXB2 ratio. Less

我们已经证明，胰腺炎患者的纯胰液中的前列腺素（PGs）和血栓素（TX）水平升高。这些发现引导我们研究PGs和TX在胰腺炎的病理生理学和治疗中的作用。基础研究：初步研究表明，雨蛙素诱导的大鼠胰腺炎最适合于本研究，应皮下注射雨蛙素（Cn）（Sigma，St. Louis，USA）10 μ g/kg，每隔1小时注射4次，在6小时处死，以定量胰腺重量、腹水、血清胰腺酶和损伤的组织学证据。在第二个实验中，测定了16，16-二甲基PGE_2（dmPGE_2）或吲哚美辛（IND）对胰腺炎的影响。皮下注射dmPGE 2（10、30或100 μ g/kg）两次（Cn注射开始前30分钟和Cn注射开始后3小时）、Cn注射开始前30分钟一次或Cn注射开始后30分钟一次。吲哚美辛（IND）（Sigma，St. Louis，USA）5 mg/kg注射给药。 ...更多信息 在Cn注射开始前1小时和注射开始后3小时皮下注射。在第三个实验中，评价dmPGE 2或IND对胰腺内源性PGs和TXB 2含量的影响。根据初步研究。Cn 10 μ g/kg注射2次，2小时后处死大鼠。在开始Cn注射前30分钟注射dmPGE 2 100 ug/kg或IND 5 mg/kg。Cn剂量诱导水肿性胰腺炎（水肿、空泡、细胞浸润）而无坏死。dmPGE 2诱导胰腺炎严重程度的剂量和时间依赖性改善。用dmPGE 2治疗前和治疗后的组合引起显著改善，而单独治疗前或治疗后仅引起轻度改善。相反，IND对上述参数产生有害影响，出现胰腺坏死。Cn诱发的胰腺炎表现为内源性PGE_2、6-koto-PGF_（1a）、TXB_2和6-keto-PGF_（1a）/TXB_2比值明显升高。IND和dmPGE 2给药导致PGE2.6-keto-PGF 1a、TXB 2、6-keto-PGF 1a/TXB 2比值和PGE 2/TXB 2比值明显下降。在dmPGE 2处理的大鼠中，内源性PGE 2的减少被外源性dmPGE 2很好地补偿;然而，6-keto-PGF 1a/TXB 2比值的降低被认为具有胰腺炎恶化的潜在风险，这取决于胰腺炎模型。相反，在IND治疗的大鼠中，6-keto-PGF 1a和6-keto-PGF 1a/TXB 2比值的降低被认为是在PGE 2和PGE 2/TXB 2比值降低的情况下引起胰腺坏死恶化的原因.临床研究：胰腺炎患者纯胰液的特征性发现是临床加重时TXB 2和TXB 2/6-keto-PGF 1a比值升高，临床改善时恢复正常。临床剂量的消炎痛既未引起胰腺炎的临床加重，也未引起PGE_2/TXB_2和6-keto-PGF_（1a）/TXB_2比值的显著降低，提示PGE_2对大鼠胰腺炎具有保护作用。然而，目前临床上使用外源性PGE 2治疗胰腺炎是不合理的，因为胰腺炎发作后给予PGE 2的疗效不足，并且存在6-keto-PGF 1a/TXB 2比值降低的潜在风险。常用于止痛的吲哚美辛应谨慎使用，因为内源性6-keto-PGF 1a、6-keto-PGF 1a/TXB 2比值降低可能导致胰腺炎恶化。前列腺素E2。PGE 2/TXB 2比值。少

项目成果

壼井 圭一,原田 英雄: "砠炎の病態におけるプロスタグテンディンの役割(第2報)" 膵臓.

Keiichi Shirai、Hideo Harada：“前列腺素在咽炎病理学中的作用（第二次报告）”胰腺。

原田 英雄,越智 浩二,田中 淳太郎,他: "ラットのセルレイン膵炎に対する16ー16ーdimethyl prostaglzndin E_2の効果" 膵臓.

Hideo Harada、Koji Ochi、Juntaro Tanaka 等人：“16-16-二甲基前列腺素 E_2 对大鼠雨伞素胰腺炎的影响”胰腺。

Harada H, Ochi K, Tanaka J, et al.: "Effect of 16, 16-dimethyl prostaglandin E2 on caerulein-induced experimental pancreatitis in rats." Pancreas.

Harada H、Ochi K、Tanaka J 等人：“16, 16-二甲基前列腺素 E2 对雨蛙素诱导的大鼠实验性胰腺炎的影响”。

原田 英雄,越智 浩二,田中 淳太郎,他: "ラットのセルレイン膵炎に対するインドメサシンの効果" 膵臓.

Hideo Harada、Koji Ochi、Juntaro Tanaka 等人：“吲哚美辛对大鼠雨伞素胰腺炎的影响”胰腺。

Miyeke H,Harada H,Ochi K,Oka H,Ishibashi T,Kimura I: "Free Fatty Acids in Human Pure Pancreatic Juice." Pancreas. 3. 213-219 (1988)

Miyeke H，Harada H，Ochi K，Oka H，Ishibashi T，Kimura I：“人纯胰液中的游离脂肪酸。”