ACTIVATION OF GENES FOR SPASMOLYTIC PEPTIDE, TRANSFORMING-GROWTH-FACTOR-ALPHA AND FOR CYCLOOXYGENASE (COX)-1 AND COX-2 DURING GASTRIC ADAPTATION TO ASPIRIN DAMAGE IN RATS

Background: NSAIDs, such as aspirin (ASA), cause widespread mucosal da mage, but repeated ASA insults appear to induce mucosal tolerance (ada ptation) to this injury. The mechanism of the gastric adaptation to th e damage induced by ASA has not been fully explained. Aim: To determin e the role of the mucosal gene expression for spasmolitic peptide (SP) (a member of trefoil peptides) and transforming growth factor alpha ( TGF alpha) as well as for cyclooxygenase (COX)-1 and COX-2 during gast ric adaptation to ASA in rats. Methods: Gastric lesions were produced by ASA (100 mg/kg in 1.5 mt of 0.2 M HCl) applied intragastrically (i. g.) as a single dose, every day for 5 days. Control rats were given 1. 5 mt of vehicle (0.2 at HCl i.g.) as a single dose, during 5 consecuti ve days. Gastric blood now (GBF) was measured by H-2-gas clearance tec hnique and gastric mucosal specimens were taken for the assessment of cell proliferation rate in gastric mucosa by bromodeoxyuridine (BrdU) uptake, mucosal generation of prostaglandin E-2 measured by radioimmun oassay, and for expression of SP, TGF alpha COX-1 and COX-2 mRNA as de termined by RT-PCR. To quantify the relative amounts of mRNA for SP an d TGF alpha, southern blotting analysis of the PCR products was perfor med and the intensity of PCR products was compared with that of beta-a ctin used as a standard. Results: ASA applied once produced numerous g astric erosions, but with repeated ASA doses the adaptation to this NS AID developed, the area of gastric lesions being reduced by 86% after six consecutive ASA insults. This adaptation to ASA was accompanied by approximately a 90% reduction in prostaglandin E-2 biosynthesis, by a significant rise in BrdU uptake by glandular cells predominantly in t he neck region of gastric glands and by expression of SP (SP/beta-acti n ratio; 0.96 +/- 0.08 in ASA-adapted mucosa vs, 0.38 +/- 0.05 in the control mucosa) and TGF alpha (TGF alpha/beta-actin ratio: 0.97 +/- 0. 07 in ASA-adapted mucosa vs. 0.77 +/- 0.06 in the control mucosa). COX -1 expression was detected in vehicle-control gastric mucosa and after single exposure to ASA or after six consecutive ASA insults, while CO X-2 mRNA was not detected in vehicle-control gastric mucosa, but appea red after single ASA insult and was sustained after subsequent ASA dos es. Conclusions: (i) Gastric adaptation to aspirin injury involves enh anced cell proliferation which appears to be mediated by increased exp ression of SP and TGF alpha, and (ii) rapid upregulation of COX-2 expr ession following single and repeated ASA insults may represent a compe nsatory response to suppression of prostaglandin generation by this NS AID.