Importance of cytokines, nitric oxide, and apoptosis in the pathological process of necrotizing pancreatitis in rats
Importance of cytokines, nitric oxide, and apoptosis in the pathological process of necrotizing pancreatitis in rats
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DOI：
10.1097/00006676-200408000-00011
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发表时间：
2004-08-01
期刊：
影响因子：
2.9
通讯作者：
Farkas, G
中科院分区：
文献类型：
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作者：
Leindler, L;Morschl, É;Farkas, G
目的：缺血再灌注损伤参与了急性坏死性胰腺炎的病理生理过程。本研究的目的是确定在此病理过程中细胞因子、肿瘤坏死因子（TNF）和白细胞介素-6（IL-6）的产生、诱导型一氧化氮合酶（iNOS）的活化以及细胞凋亡的发展。在雄性Wistar大鼠中通过注射200穆尔的6%将牛磺胆酸注入主胰管，并暂时（15分钟）闭塞脾下动脉。6和24小时后，组织学损害进行了评估，血清淀粉酶，TNF，IL-6水平，和iNOS和胰腺和肺组织的凋亡活性进行了测定。结果：诱导胰腺炎后24小时，死亡率为63%。在此期间，血清TNF和IL-6水平持续较高（6小时和24小时后分别为50 +/- 12和58 +/- 10 U/mL以及7083 +/- 1610和6790 +/- 850 U/mL）。iNOS活性在胰腺中显示出增加的趋势，在肺中在初始增加后降低（分别在6和24小时后从4.2 +/- 0.6至5 +/- 0.4和从6.8 +/- 0.6至3.8 +/- 0.5 pmol/min/mg蛋白）。组织学检查证实为严重坏死性胰腺炎。在胰腺中，凋亡活性显著增加（6和24小时从4 +/- 4到27 +/- 5/ mm（2）），而在肺中，在坏死性胰腺炎过程中，它在最初增加后下降（在6和24小时从49 +/- 4至11 +/- 6/ mm（2））。我们的研究结果表明，导管内牛磺胆酸和缺血-再灌注引起具有高死亡率的严重急性坏死性胰腺炎并导致全身炎症反应，这似乎是细胞因子级联和iNOS激活的结果。iNOS过度产生NO的程度与胰腺和肺中的凋亡过程相对应。
Objectives: Ischemia-reperfusion injury can be involved in the pathophysiology of acute necrotizing pancreatitis. The aim of our study was to determine the production of cytokines, tumor necrosis factor (TNF) and interleukin-6 (IL-6), the activation of the inducible nitric oxide synthase ( iNOS), and the development of apoptosis during this pathologic process.Methods: Acute pancreatitis was produced in male Wistar rats by injection of 200 muL of 6% taurocholic acid into the main pancreatic duct in combination with the temporary ( 15 minutes) occlusion of the inferior splenic artery. Six and 24 hours later, the histologic damage was evaluated, and serum amylase, TNF, IL-6 levels, and iNOS and apoptotic activity from pancreatic and pulmonary tissues were determined.Results: Twenty-four hours after the induction of pancreatitis, the mortality rate was 63%. During this period, the serum TNF and IL-6 levels were permanently high ( 50 +/- 12 and 58 +/- 10 U/mL and 7083 +/- 1610 and 6790 +/- 850 U/mL after 6 and 24 hours, respectively). The iNOS activity showed an increasing tendency in the pancreas, and a decrease following an initial increase in the lung ( from 4.2 +/- 0.6 to 5 +/- 0.4 and from 6.8 +/- 0.6 to 3.8 +/- 0.5 pmol/min/mg protein after 6 and 24 hours, respectively). Histologic examination confirmed severe necrotizing pancreatitis. In the pancreas, the apoptotic activity increased significantly ( from 4 +/- 4 to 27 +/- 5/ mm(2) at 6 and 24 hours), while in the lungs, following an initial increase it declined during the course of necrotizing pancreatitis ( from 49 +/- 4 to 11 +/- 6/ mm(2) at 6 and 24 hours).Conclusion: Our results indicate that intraductal taurocholic acid and ischemia-reperfusion provokes severe acute necrotizing pancreatitis with a high mortality rate and leads to systemic inflammatory reaction, which appears to be the consequence of the activation of the cytokine cascade and iNOS. The degree of NO overproduction by iNOS corresponds with the apoptotic process in the pancreas and the lung.