BASE VARIANT OF HUMAN PANCREATIC SECRETORY TRYPSIN-INHIBITOR IN HEALING OF STRESS-INDUCED GASTRIC-LESIONS IN RATS

Pancreatic secretory trypsin inhibitor (PSTI) is an inhibitor of serin e-proteinases including pancreatic trypsin that prevents excessive dig estion of the gastrointestinal mucus, but its role in the mechanism of mucosal defense has been little studied. This study was designed to d etermine the effect of base variant of human PSTI (R44S-PSTI) on gastr ic secretion, healing of gastric lesions induced by stress and the exp ression of PSTI during mucosal recovery from stress lesions. Recombina nt R44S-PSTI was obtained using by site-directed mutagenesis due to re placement of arginine by serine that led to longer half life of this p eptide than its natural form. Stress ulcerations were induced by expos ure of rats to a standard 3.5 h of water immersion and restraint stres s with or without pretreatment with vehicle or R44S-PSTI (0.1 mg/kg) a pplied s.c. 39 min before and immediately after the end of stress. Rat s were then sacrificed immediately (time 0) and at 6 h or 12 h after t he termination of stress. The gastric blood flow (GBF) was measured by H-2-gas clearance technique at each time period and gastric mucosal s amples were excised for assessment of PSTI immunohistochemical express ion and PSTI messenger RNA by reverse transcriptase polymerase chain r eaction (RT-PCR) and Southern hybridization. Stress produced numerous gastric lesions and decreased the GBF by about 30% as compared to the respective value in vehicle-treated non-stressed gastric mucosa. R44S- PSTI given s.c. in graded doses (0.01-1 mg/kg) inhibited dose-dependen tly gastric acid and pepsin outputs, in rats with gastric fistula and accelerated the healing of stress-induced gastric lesions significantl y. The healing effects of R44S-PSTI (0.1 mg/kg s.c.) recorded at 6 h a nd 12 h after the end of stress were accompanied by a significant rise in the GBF. The expression of PSTI mRNA in the intact mucosa was weak , but following exposure to stress it was significantly augmented to r each the highest observed value at 6 h after the stress. We conclude t hat (1) base variant of human PSTI accelerates healing of stress-induc ed gastric lesions probably due to its antisecretory activity and enha ncement of mucosal blood flow and (2) the expression of genes for PSTI plays an important role in the mechanism of mucosal recovery from gas tric lesions induced by stress. (C) 1998 Elsevier Science B.V. All rig hts reserved.