The pathogenesis of L-arginine-induced acute necrotizing pancreatitis:: Inflammatory mediators and endogenous cholecystokinin
The pathogenesis of L-arginine-induced acute necrotizing pancreatitis:: Inflammatory mediators and endogenous cholecystokinin
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DOI：
10.1016/s0928-4257(99)00104-7
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发表时间：
2000-01-01
影响因子：
--
通讯作者：
Lonovics, J
中科院分区：
文献类型：
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作者：
Czakó, L;Takács, T;Lonovics, J
本研究旨在探讨氧自由基、细胞因子和内源性胆囊收缩素在L-精氨酸（Arg）诱导的大鼠急性胰腺炎发病中的作用。检测胰腺组织丙二醛（MDA）、谷胱甘肽过氧化物酶（GPx）、过氧化氢酶（CAT）、超氧化物歧化酶（Mn-和Cu，Zn-SOD）、血清肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和胆囊收缩素（CCK）水平，并评价黄嘌呤氧化酶抑制剂别嘌呤醇和新型CCK受体拮抗剂KSG-504的保护作用。在雄性Wistar大鼠中，通过在1小时间隔内腹膜内注射2 x 250 mg/100 g体重的Arg（20%的0.15 M NaCl溶液）诱导急性胰腺炎。对照组大鼠接受相同量的甘氨酸。200 mg.kg（-1）别嘌呤醇30分钟前第一次精氨酸治疗或50 mg.kg（-1）KSG-504 30分钟前和6，18和36小时后第一次精氨酸注射皮下给药。分别于给药后6、12、24和48 h处死大鼠，通过血清淀粉酶水平升高和显微镜下观察到的典型炎症特征证实为急性胰腺炎。血清淀粉酶水平在注射Arg后24 h达到峰值（30800 ± 3813），对照组为6382 ± 184 U·L-1，48 h恢复正常。MDA的组织浓度在24小时显著升高，并在48小时达到峰值（5.00 +/- 1.75对对照中的0.28 +/- 0.0.5 nM.mg（-1）蛋白质）。与对照组相比，注射Arg后6 h和12 h，过氧化氢酶和Mn-SOD活性显著降低，GPx活性显著降低，Cu，Zn-SOD活性显著降低。与对照组相比，TNF-α和IL-6水平均已升高，在12 h时显著升高，在24 h时达到峰值（分别为19.1 +/- 7.9 U.mL（-1）和57.6 +/- 11.2 pg.mL（-1）vs 3.1 +/- 0.8 U.mL（-1）和15.2 +/- 3.1 pg.mL（-1））。血浆CCK水平无明显变化。别嘌呤醇治疗显著降低了血清淀粉酶升高（24 h时为12.631 +/- 2.257 U.L-1），防止了组织MDA浓度升高（48 h时为0.55 +/- 0.09 nM.mg（-1）蛋白），并显著改善了Arg给药后48 h的胰腺水肿、坏死和炎症。KSG-504给药对组织病理学变化的发展没有产生任何有益的影响，也没有改变血清淀粉酶或细胞因子水平。氧自由基和细胞因子参与了Arg诱导的急性胰腺炎的发病机制，而内源性CCK似乎没有发挥作用。(C)2000 Elsevier Science Ltd.由Editions scientifiques et medicales Elsevier SAS出版。
This study was aimed at an assessment of the role of oxygen-derived free radicals, cytokines and endogenous cholecystokinin (CCK) in the pathogenesis of L-arginine (Arg)-induced acute pancreatitis in rat. We measured the levels of malonyl dialdehyde (MDA), glutathione peroxidase (GPx), catalase and superoxide dismutase (Mn- and Cu, Zn-SOD) in pancreatic tissue, the serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and CCK, and evaluated the protective effect of the xanthine oxidase inhibitor allopurinol and a novel CCK receptor antagonist KSG-504. Acute pancreatitis was induced in male Wistar rats by injecting 2 x 250 mg/100 g body weight of Arg intraperitoneally in an 1-h interval, as a 20% solution in 0.15 M NaCl. Control rats received the same quantity of glycine. 200 mg.kg(-1) allopurinol 30 min before the first Arg treatment or 50 mg.kg(-1) KSG-504 30 min before and 6, 18 and 36 h after the first Arg injection was administered subcutaneously. Rats were killed at 6, 12, 24 and 48 h following Arg administration, and acute pancreatitis was confirmed by a serum amylase level elevation and typical inflammatory features observed microscopically. The serum level of amylase reached the peak level at 24 h after the Arg injection (30 800 +/- 3 813 Versus 6 382 +/- l84 U.L-1 in the control) and normalized at 48 h. The tissue concentration of MDA was significantly elevated at 24 h, and reached the peak value at 48 h (5.00 +/- 1.75 versus 0.28 +/- 0.0.5 nM.mg(-1) protein in the control). The catalase and Mn-SOD activities were significantly decreased throughout the study, while the GPx activity was significantly reduced at 6 and 12 h, and the Cu, Zn-SOD activity was significantly lower at 12 h after the Arg injection as compared with the controls. Both the TNF-cr and the IL-6 levels were already elevated si,significantly at 12 h and peak at 24 h versus the controls (19.1 +/- 7.9 U.mL(-1) and 57.6 +/- 11.2 pg.mL(-1) versus 3.1 +/- 0.8 U.mL(-1) and 15.2 +/- 3.1 pg.mL(-1), respectively). No significant changes in plasma CCK levels were observed. Allopurinol treatment markedly reduced the serum amylase elevation (12.631 +/- 2.257 U.L-1 at 24 h), prevented the increase in tissue MDA concentration (0.55 +/- 0.09 nM.mg(-1) protein at 48 h) and significantly ameliorated the pancreatic edema, necrosis and inflammation at 48 h after Arg administration. KSG-504 administration did not exert any beneficial effect on the development of histopathological changes neither modified the serum amylase or cytokine levels. Oxygen-derived free radicals and cytokines are involved, while endogenous CCK does not seem to play a role in the pathogenesis of Arg-induced acute pancreatitis. (C) 2000 Elsevier Science Ltd. Published by Editions scientifiques et medicales Elsevier SAS.