ABSTRACT
BACKGROUND: In acute pancreatitis, two different types of secretory phospholipase A2 (PLA2) have been found: pancreatic type I PLA2 and non-pancreatic type II PLA2. In this study a potent new PLA2 inhibitor effective against type II PLA2 was used in an experimental model of acute pancreatitis. METHODS: In 70 rats the efficacy of the compound was analysed in two experimental models of acute pancreatitis: cerulein- and taurocholate-induced acute pancreatitis, imitating mild and severe disease respectively. Serum rat type I PLA2 protein concentration and type I and type II PLA2 catalytic activities were measured while giving the inhibitor therapeutically. In a prophylactic protocol the effect on histology was analysed. RESULTS: In the taurocholate model, type II PLA2 activity was found to be nine-fold higher than in the cerulein model (P < 0.002), whereas the activity of type I PLA2 was not increased. The inhibitor significantly decreased serum type II PLA2 activity in the taurocholate model of acute pancreatitis (P < 0.05) but type I PLA2 protein concentration and type I PLA2 activity were not affected. The inhibitor also reduced histological tissue damage, with significant differences at 3 and 12 h (P < 0.01). CONCLUSION: The PLA2 inhibitor significantly reduced type II PLA2 activity and was able to protect the pancreas against tissue damage. PLA2 inhibition offers the possibility of a treatment for acute pancreatitis.
Subject(s)
Enzyme Inhibitors/therapeutic use , Pancreatitis/drug therapy , Phospholipases A/antagonists & inhibitors , Acute Disease , Animals , Ceruletide , Edema , Female , Necrosis , Pancreatitis/chemically induced , Pancreatitis/enzymology , Pancreatitis/pathology , Phospholipases A2 , Rats , Rats, Wistar , Taurocholic AcidABSTRACT
BACKGROUND: In human acute pancreatitis two different types of secretory phospholipase A2 (PLA2) have been found. AIM: To analyse the specific pattern of distribution of these PLA2 activities and their pathophysiological role in experimental acute pancreatitis. SUBJECTS AND METHODS: Catalytic activities of secretory type I (pancreatic) and type II (non-pancreatic) PLA2 and the protein concentration of immunoreactive pancreatic PLA2 (IR-PLA2) in serum and pancreatic tissue of rats with cerulein (mild form) and sodium taurocholate (severe form) induced acute pancreatitis were determined. RESULTS: Cerulein infusion caused a significant increase in type I PLA2 activity (p < 0.01) and IR-PLA2 protein concentration (p < 0.01) in serum and pancreas, whereas type II PLA2 activity remained unchanged during the 12 hour observation period. Histology showed no significant tissue destruction. In sodium taurocholate induced acute pancreatitis type II PLA2 activity significantly increased, reaching values over 10-fold higher than controls (p < 0.01), whereas IR-PLA2 protein concentration and type I PLA2 activity were only marginally increased. In this severe model of acute pancreatitis significantly lower values were detected than in the control pancreas (p < 0.002) for PLA2 activity and IR-PLA2 protein concentration. Histology showed parenchymal and fat necroses with haemorrhage, oedema, and inflammatory cell infiltration. CONCLUSIONS: Type I PLA2 activity is dependent on the IR-PLA2 protein concentration in serum and pancreatic tissue. The type II PLA2 activity is not stimulated by cerulein, which indicates an extra-acinar origin of this enzyme. Type II PLA2 activity is significantly increased in sodium taurocholate induced acute pancreatitis indicating its role in the local necrotising process and involvement in the systemic effects in severe acute pancreatitis.
