Base variant of human pancreatic secretory trypsin inhibitor in healing of stress-induced gastric lesions in rats.

Abstract

Pancreatic secretory trypsin inhibitor (PSTI) is an inhibitor of serine-proteinases including pancreatic trypsin that prevents excessive digestion of the gastrointestinal mucus, but its role in the mechanism of mucosal defense has been little studied. This study was designed to determine the effect of base variant of human PSTI (R44S-PSTI) on gastric secretion, healing of gastric lesions induced by stress and the expression of PSTI during mucosal recovery from stress lesions. Recombinant R44S-PSTI was obtained using by site-directed mutagenesis due to replacement of arginine by serine that led to longer half life of this peptide than its natural form. Stress ulcerations were induced by exposure of rats to a standard 3.5 h of water immersion and restraint stress with or without pretreatment with vehicle or R44S-PSTI (0.1 mg/kg) applied s.c. 30 min before and immediately after the end of stress. Rats were then sacrificed immediately (time 0) and at 6 h or 12 h after the termination of stress. The gastric blood flow (GBF) was measured by H2-gas clearance technique at each time period and gastric mucosal samples were excised for assessment of PSTI immunohistochemical expression and PSTI messenger RNA by reverse transcriptase polymerase chain reaction (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-dependently gastric acid and pepsin outputs, in rats with gastric fistula and accelerated the healing of stress-induced gastric lesions significantly. The healing effects of R44S-PSTI (0.1 mg/kg s.c.) recorded at 6 h and 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 reach the highest observed value at 6 h after the stress. We conclude that (1) base variant of human PSTI accelerates healing of stress-induced gastric lesions probably due to its antisecretory activity and enhancement of mucosal blood flow and (2) the expression of genes for PSTI plays an important role in the mechanism of mucosal recovery from gastric lesions induced by stress.

• Authors: P Ch Konturek, T Brzozowski, S J Konturek, A Taut, P Pierzchalski, G Elia, R Pajdo, S Yagi, E G Hahn
• Journal: Regulatory peptides (Regul Pept) Vol. 77 Issue 1-3 Pg. 95-103 (Oct 16 1998) ISSN: 0167-0115 [Print] Netherlands
• PMID: 9809802 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Recombinant Proteins
• Trypsin Inhibitor, Kazal Pancreatic
• Trypsin

Topics

• Animals
• Blotting, Southern
• Gastric Mucosa (pathology)
• Humans
• Immersion
• Immunohistochemistry
• Male
• Mutagenesis, Site-Directed (genetics)
• RNA, Messenger (metabolism)
• Rats
• Rats, Wistar
• Recombinant Proteins (therapeutic use)
• Regional Blood Flow (drug effects)
• Stomach Diseases (therapy)
• Stress, Physiological (physiopathology)
• Trypsin (pharmacology)
• Trypsin Inhibitor, Kazal Pancreatic (genetics, therapeutic use)