title: 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.
abstract: BACKGROUND
  NSAIDs, such as aspirin (ASA), cause widespread mucosal damage, but repeated ASA insults appear to induce mucosal tolerance (adaptation) to this injury. The mechanism of the gastric adaptation to the damage induced by ASA has not been fully explained.
  
  
  OBJECTIVE
  To determine 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 gastric adaptation to ASA in rats.
  
  
  METHODS
  Gastric lesions were produced by ASA (100 mg/kg in 1.5 mL of 0.2 M HCl) applied intragastrically (i.g.) as a single dose. every day for 5 days. Control rats were given 1.5 mL of vehicle (0.2 M HCl i.g.) as a single dose, during 5 consecutive days. Gastric blood flow (GBF) was measured by H2-gas clearance technique and gastric mucosal specimens were taken for the assessment of cell proliferation rate in gastric mucosa by bromodeoxyuridine (BrdU) uptake, mucosal generation of prostaglandin E2 measured by radioimmunoassay, and for expression of SP, TGF alpha COX-1 and COX-2 mRNA as determined by RT-PCR. To quantify the relative amounts of mRNA for SP and TGF alpha, southern blotting analysis of the PCR products was performed and the intensity of PCR products was compared with that of beta-actin used as a standard.
  
  
  RESULTS
  ASA applied once produced numerous gastric erosions, but with repeated ASA doses the adaptation to this NSAID 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 E2 biosynthesis, by a significant rise in BrdU uptake by glandular cells predominantly in the neck region of gastric glands and by expression of SP (SP/beta-actin 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 COX-2 mRNA was not detected in vehicle-control gastric mucosa, but appeared after single ASA insult and was sustained after subsequent ASA doses.
  
  
  CONCLUSIONS
  (i) Gastric adaptation to aspirin injury involves enhanced cell proliferation which appears to be mediated by increased expression of SP and TGF alpha, and (ii) rapid upregulation of COX-2 expression following single and repeated ASA insults may represent a compensatory response to suppression of prostaglandin generation by this NSAID.
authors.affiliation: Department of Medicine I, University Erlangen-Nuremberg, Germany. mpogonow@cyf-kr.edu.pl
authors.forename: P C
authors.initials: PC
authors.lastname: Konturek
authors.forename: T
authors.initials: T
authors.lastname: Brzozowski
authors.forename: P
authors.initials: P
authors.lastname: Pierzchalski
authors.forename: S
authors.initials: S
authors.lastname: Kwiecien
authors.forename: R
authors.initials: R
authors.lastname: Pajdo
authors.forename: E G
authors.initials: EG
authors.lastname: Hahn
authors.forename: S J
authors.initials: SJ
authors.lastname: Konturek
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000633:toxicity*; D001241:Aspirin / Q000494:pharmacology / Q000633:toxicity*; D002455:Cell Division; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D015870:Gene Expression; D008297:Male; D010455:Peptides / Q000235:genetics* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010455:Peptides; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin