DECREASED MORTALITY OF SEVERE ACUTE-PANCREATITIS AFTER PROXIMAL CYTOKINE BLOCKADE
DECREASED MORTALITY OF SEVERE ACUTE-PANCREATITIS AFTER PROXIMAL CYTOKINE BLOCKADE
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DOI：
10.1097/00000658-199506000-00002
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发表时间：
1995-06-01
影响因子：
9
通讯作者：
CAREY, LC
中科院分区：
文献类型：
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作者：
NORMAN, JG;FRANZ, MG;CAREY, LC
目的探讨白细胞介素-1受体拮抗剂（IL-1ra）降低实验性急性胰腺炎病死率的作用。我们测量了炎症细胞因子级联反应及其对胰腺形态的后续影响，以确定这些肽在介导胰腺损伤中的作用。以往的研究表明，急性胰腺炎期间促炎细胞因子大量产生，IL-1受体水平的阻断可显著降低胰腺的内在损伤。对生存率的后续影响尚不清楚。方法用缺乏胆碱、补充乙硫氨酸（CDE）的饲料喂养72小时，诱导急性出血性坏死性胰腺炎致死性小鼠。为了确定死亡率，将动物分为3组，每组45只动物：对照组。生理盐水100/ μ L，每6小时腹腔注射，连续5天；IL-1ra早期小鼠每6小时腹腔注射重组白细胞介素-1受体拮抗剂15 mg/kg，从时间0开始持续5天；IL-1ra晚期小鼠在引入CDE饮食后1.5天开始，每6小时腹腔注射IL-1ra 15 mg/kg，持续3.5天。同时进行平行实验，每组至少29只动物，每天处死，比较血清淀粉酶、脂肪酶、IL-1、IL-6、肿瘤坏死因子- α、IL-1ra、胰腺湿重和盲法组织病理学分级。结果对照组10天死亡率为73%。早期和晚期给予IL-1 ra导致死亡率分别下降到44%和51% （p均< 0.001）。白细胞介素-1拮抗剂也与IL-1ra早期和晚期胰腺湿重、血清淀粉酶和脂肪酶升高的显著减弱相关（均p < 0.05）。所有对照动物的炎症细胞因子迅速升高，在第3天达到最高水平。然而，il -1ra处理的动物表现出这些介质的钝化上升（均p < 0.05）。盲法组织学分级显示，接受拮抗剂治疗的动物胰腺炎的严重程度总体上有所下降。结论早期和晚期阻断IL-1受体水平的细胞因子级联可显著降低重症急性胰腺炎的死亡率。其机制似乎包括全身炎症细胞因子的衰减和胰腺破坏的减少。
ObjectiveThis study determined the ability of interleukin-1 receptor antagonist (IL-1ra) to decrease the mortality of experimental acute pancreatitis. The response of the inflammatory cytokine cascade and its subsequent effects on pancreatic morphology were measured to determine the role of these peptides in mediating pancreatic injury.Summary Background DataPrevious studies have shown that proinflammatory cytokines are produced in large amounts during acute pancreatitis and that blockade at the level of the IL-1 receptor significantly decreases intrinsic pancreatic damage. The subsequent effect on survival is not known.MethodsA lethal form of acute hemorrhagic necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethionine supplemented (CDE) diet for 72 hours. For determination of mortality, the animals were divided into 3 groups of 45 animals each: control subjects received. 100/mu L normal saline intraperitoneally every 6 hours for 5 days; IL-1ra early mice received recombinant interleukin-1 receptor antagonist 15 mg/kg intraperitoneally every 6 hours for 5 days beginning at time O; IL-1ra late mice received IL-1ra 15 mg/kg intraperitoneally every 6 hours for 3.5 days beginning 1.5 days after introduction of the CDE diet. A parallel experiment was conducted simultaneously with a minimum of 29 animals per group, which were sacrificed daily for comparisons of serum amylase, lipase, IL-1, IL-6, tumor necrosis factor-alpha, IL-1ra, pancreatic wet weight, and blind histopathologic grading.ResultsThe 10-day mortality in the untreated control group was 73%. Early and late IL-1 ra administration resulted in decreases of mortality to 44% and 51%, respectively (both p < 0.001). interleukin-1 antagonism also was associated with a significant attenuation in the rise in pancreatic wet weight and serum amylase and lipase in both early and late IL-1ra groups (all p < 0.05). All control animals developed a rapid elevation of the inflammatory cytokines, with maximal levels reached on day 3. The IL-1ra-treated animals, however, demonstrated a blunted rise of these mediators (all p < 0.05). Blind histologic grading revealed an overall decrease in the severity of pancreatitis in those animals receiving the antagonist.ConclusionsEarly dr late blockade of the cytokine cascade at the level of the IL-1 receptor significantly decreases the mortality of severe acute pancreatitis. The mechanism by which this is accomplished appears to include attenuation of systemic inflammatory cytokines and decreased pancreatic destruction.