Yamano M, Umeda M, Miyata K, Yamada T
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 1998 May;357(5):558-64. doi: 10.1007/pl00005208.
A severe acute pancreatitis was produced by intraperitoneal injection of lipopolysaccharide (LPS) in rats with preexisting hemorrhagic and necrotizing pancreatitis induced by retrograde injection of a 5% taurocholate plus 1% trypsin solution into the pancreatic duct. Mortality and time-course changes in pancreatic, hepatic, renal and pulmonary functions, and organ myeloperoxidase (MPO) levels were examined in this model. LPS at an intraperitoneal dose of 30 mg/kg, which scarcely caused death and had no marked effect on serum parameters and organ MPO levels in rats without pancreatitis, increased the mortality in rats with taurocholate plus trypsin-induced pancreatitis. Pancreatic weight and ascitic volume increased in rats with taurocholate plus trypsin-induced pancreatitis regardless of the presence or absence of LPS. Serum amylase and lipase levels were also significantly increased in rats with induced pancreatitis, but was higher in the group given LPS. Serum glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN) and creatinine levels were significantly elevated in LPS-treated rats with induced pancreatitis, whereas levels in rats with induced pancreatitis not given LPS were only slightly elevated. Renal weight was also significantly increased in rats with induced pancreatitis despite the presence or absence of LPS. In LPS-treated rats with induced pancreatitis, the arterial oxygen pressure, pulmonary weight and pulmonary MPO level were significantly elevated. However, the MPO level in the kidney in these rats was not different from that in control rats, indicating that the renal dysfunction was not produced by the infiltration of neutrophils into the kidney. Increase in the pancreatic MPO level was observed in rats with induced pancreatitis, but combination treatment with LPS did not raise it. Protective effects of prophylactic treatment of 2-(3-methylsulfonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-( 3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (compound 1), a neutrophil elastase inhibitor, and trifluoroacetyl-L-lysyl-L-alaninanilide hydrochloride (compound 2), a pancreatic elastase inhibitor, on mortality were also examined in this model. Results were compared with that of the combined treatment of compound 1 and compound 2. In LPS-treated rats with taurocholate plus trypsin-induced pancreatitis, the combined treatment of compound 1 (2 mg/kg/h) and compound 2 (30 mg/kg/h) significantly reduced mortality, whereas single treatment of compound 1 or compound 2 did not show the beneficial effect. These results suggest that marked hepatic and renal dysfunction accompanies pancreatitis in this pancreatitis model rats, which may be good models for acute pancreatitis in humans. It is also suggested that neutrophil and pancreatic elastases may be synergistically involved in the pathogenesis of acute pancreatitis in this model.
通过向预先经逆行胰管注射5%牛磺胆酸盐加1%胰蛋白酶溶液诱导出血性坏死性胰腺炎的大鼠腹腔内注射脂多糖（LPS），制备重症急性胰腺炎模型。在此模型中，检测死亡率以及胰腺、肝脏、肾脏和肺功能的时间进程变化，以及器官髓过氧化物酶（MPO）水平。腹腔注射剂量为30 mg/kg的LPS，在无胰腺炎的大鼠中几乎不引起死亡，对血清参数和器官MPO水平也无明显影响，但可增加牛磺胆酸盐加胰蛋白酶诱导的胰腺炎大鼠的死亡率。无论是否存在LPS，牛磺胆酸盐加胰蛋白酶诱导的胰腺炎大鼠的胰腺重量和腹水量均增加。诱导性胰腺炎大鼠的血清淀粉酶和脂肪酶水平也显著升高，但给予LPS的组更高。LPS处理的诱导性胰腺炎大鼠的血清谷草转氨酶（GOT）、谷丙转氨酶（GPT）、血尿素氮（BUN）和肌酐水平显著升高，而未给予LPS的诱导性胰腺炎大鼠的这些水平仅略有升高。无论是否存在LPS，诱导性胰腺炎大鼠的肾脏重量也显著增加。在LPS处理的诱导性胰腺炎大鼠中，动脉血氧分压、肺重量和肺MPO水平显著升高。然而，这些大鼠肾脏中的MPO水平与对照大鼠无异，表明肾功能障碍并非由中性粒细胞浸润肾脏所致。诱导性胰腺炎大鼠的胰腺MPO水平升高，但LPS联合处理并未使其进一步升高。还在此模型中检测了中性粒细胞弹性蛋白酶抑制剂2-(3-甲基磺酰氨基-2-氧代-6-苯基-1,2-二氢-1-吡啶基)-N-(3,3,3-三氟-1-异丙基-2-氧代丙基)乙酰胺（化合物1）和胰腺弹性蛋白酶抑制剂三氟乙酰-L-赖氨酰-L-丙氨酰苯胺盐酸盐（化合物2）预防性治疗对死亡率的保护作用。将结果与化合物1和化合物2联合治疗的结果进行比较。在LPS处理的牛磺胆酸盐加胰蛋白酶诱导的胰腺炎大鼠中，化合物1（2 mg/kg/h）和化合物2（30 mg/kg/h）联合治疗显著降低死亡率，而单独使用化合物1或化合物2治疗未显示出有益效果。这些结果表明，在此胰腺炎模型大鼠中，胰腺炎伴有明显的肝肾功能障碍，这可能是人类急性胰腺炎的良好模型。还表明中性粒细胞弹性蛋白酶和胰腺弹性蛋白酶可能在该模型急性胰腺炎的发病机制中协同起作用。
