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.