Timing of tumor necrosis factor antagonism is critical in determining outcome in murine lethal acute pancreatitis
Timing of tumor necrosis factor antagonism is critical in determining outcome in murine lethal acute pancreatitis
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DOI：
10.1016/s0039-6060(96)80072-9
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发表时间：
1996-09-01
期刊：
影响因子：
3.8
通讯作者：
Franz, MG
中科院分区：
文献类型：
--
作者：
Norman, JG;Fink, GW;Franz, MG
背景在重症急性胰腺炎期间，肿瘤坏死因子（TNF）在胰腺、肺和肝脏内大量产生，并且被认为介导该疾病的许多典型有害后果。对TNF拮抗作用的益处的研究表明，TNF也可以介导对宿主具有保护作用的过程。随着时间在这些不同的观点中发挥作用的假设，TNF拮抗无论是免疫或治疗的重组形式的可溶性I型TNF受体（TNFbp）在致死模型的坏死性胰腺炎诱导喂养胆碱缺乏饮食。在390只雌性小鼠中测定10天的死亡率，所述小鼠被分成三组：对照组、TNFbp早期组（时间，0至5天）和TNFbp晚期组（时间，1.5至5天）。每天评估胰腺炎的严重程度和细胞因子的产生。对照组中的动物具有75%的死亡率，其通过预防性TNF阻断而显著降低（64%，p < 0.05）。延迟TNF拮抗作用直到血清细胞因子升高和胰腺炎明显时，死亡率降低至42%（与对照组相比p <0.001，与早期相比p < 0.01）。早期和晚期TNF阻断可降低胰腺水肿和血清淀粉酶、脂肪酶、白细胞介素-1和白细胞介素-6（均p < 0.05），但不能降低TNF。晚期拮抗作用通常导致所有这些参数的最大衰减。通过给予可溶性TNF受体阻断TNF可减轻胰腺炎的严重程度，减少相关炎性细胞因子的产生，并显著改善存活率。延迟拮抗作用直到胰腺炎明显并且循环细胞因子升高但尚未达到最大值似乎比简单的预防性TNF拮抗作用更具保护性。
Background. Tumor necrosis factor (TNF) is produced in large amounts within the pancreas, lungs, and liver during severe acute pancreatitis and is believed to mediate many of the detrimental consequences typical of this disease. Investigations into the benefit of TNF antagonism have suggested that TNF may also mediate processes that are protective to the host.Methods. With the hypothesis that timing plays a role in these dissenting views, TNF was antagonized either prophylactically or therapeutically with a recombinant form of the soluble type I TNF receptor (TNFbp) during a lethal model of necrotizing pancreatitis induced by feeding a choline-deficient diet. Mortality was determined for 10 days in 390 female mice divided into three groups: control, TNFbp early (time, 0 to 5 days), and TNFbp late (time, 1.5 to 5 days). Pancreatitis severity and cytokine production were assessed daily.Results. Animals in the control group had a 75% mortality rate that was significantly decreased by prophylactic TNF blockage (64%, p < 0.05). Delaying TNF antagonism until serum cytokines were elevated and pancreatitis was manifest decreased mortality to 42% (p < 0.001 versus control, p < 0.01 versus early). Early and late TNF blockade decreased pancreatic edema and serum amylase, lipase, interleukin-1, and interleukin-6 (all p < 0.05) but not TNF. Late antagonism typically resulted in the greatest attenuation of all these parameters.Conclusions. Blockade of TNF by the administration of a soluble TNF receptor attenuates the severity of pancreatitis, decreases the production of associated inflammatory cytokines, and significantly improves survival. Delaying antagonism until pancreatitis is manifest and circulating cytokines are elevated but not yet maximal appears to be more protective than simple prophylactic TNF antagonism.