Cosen-Binker Laura Iris, Binker Marcelo Gustavo, Cosen Rodica, Negri Gustavo, Tiscornia Osvaldo
Programa de Estudios Pancreáticos, Hospital de Clínicas, Departamento de Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
Dig Dis Sci. 2006 May;51(5):915-25. doi: 10.1007/s10620-005-9052-6. Epub 2006 May 3.
Leukocyte activation, inflammatory up-regulation, and microcirculatory disruption associated with ischemia-reperfusion injury are hallmarks in the pathogenesis of acute pancreatitis (AP). NO donors ensure microvascular integrity, while glucocorticoids act as anti-inflammatory and immune modulator drugs. AP was induced by the biliopancreatic duct outlet exclusion-closed duodenal loops (BPDOE-CDLs) model. Treatment with hydrocortisone (6 mg/kg) or prednisolone (0.5 mg/kg) alone or together with DETA-NO (0.5 mg/kg) was done (a)1 hr pre or (b)1 hr post, or (c) 1 hr pre and 4 hr post ,or (d) 4 hr post triggering AP. NOS inhibition by L-NAME (15 mg/kg) and glucocorticoid receptor blockage by mifepristone (3 mg/kg) was considered. AP severity was assessed by biochemical and histopathological analyses. Treatment with glucocorticoids together with DETA-NO 1 hr pre and 4 hr post BPDOE-CDLs reduced serum amylase, lipase, C-reactive protein, IL-6, IL-10, hsp72, and 8-isoprostane as well as pancreatic and lung myeloperoxidase. Acinar and fat necrosis, hemorrhage, and neutrophil infiltrate were also decreased. Hydrocortisone together with DETA-NO rendered the best results. We conclude that AP severity was significantly diminished by glucocorticoids associated with DETA-NO, with the optimal dose and time point of administration being crucial to provide adequate protection against AP.
与缺血再灌注损伤相关的白细胞活化、炎症上调和微循环破坏是急性胰腺炎（AP）发病机制的标志。一氧化氮供体可确保微血管完整性，而糖皮质激素则作为抗炎和免疫调节药物。通过胆胰管出口结扎-封闭十二指肠袢（BPDOE-CDLs）模型诱导AP。分别于诱导AP前1小时、诱导AP后1小时、诱导AP前1小时及诱导AP后4小时、诱导AP后4小时给予氢化可的松（6mg/kg）或泼尼松龙（0.5mg/kg）单独或联合DETA-NO（0.5mg/kg）进行治疗。同时考虑用L-NAME（15mg/kg）抑制一氧化氮合酶及用米非司酮（3mg/kg）阻断糖皮质激素受体。通过生化和组织病理学分析评估AP的严重程度。在BPDOE-CDLs模型诱导前1小时及诱导后4小时给予糖皮质激素联合DETA-NO治疗可降低血清淀粉酶、脂肪酶、C反应蛋白、IL-6、IL-10、hsp72和8-异前列腺素水平，以及胰腺和肺组织中的髓过氧化物酶活性。腺泡和脂肪坏死、出血及中性粒细胞浸润也减少。氢化可的松联合DETA-NO治疗效果最佳。我们得出结论，糖皮质激素联合DETA-NO可显著减轻AP的严重程度，给药的最佳剂量和时间点对于提供充分的AP防护至关重要。
