title: COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice.
abstract: OBJECTIVE
  The pathogenesis of nonsteroidal anti-inflammatory drug-induced enteropathy is controversial, but it is thought that cyclooxygenase-1 (COX-1) inhibition is of pivotal importance. We compared small intestinal function and morphology in untreated wild-type, COX-1- and COX-2-deficient mice and the effect of indomethacin, selective COX-1 (SC-560), and COX-2 (celecoxib) inhibition.
  
  
  METHODS
  Intestinal permeability ((51)CrEDTA), inflammation (fecal granulocyte marker protein), prostaglandin E(2) (PGE(2)) levels, and macroscopic and microscopic appearances were assessed at baseline and after the drugs.
  
  
  RESULTS
  COX-1(-/-) animals were normal except for a 97% decrease in intestinal PGE(2) levels. COX-1(+/+) and COX-1(-/-) animals reacted in a similar way to indomethacin. However, celecoxib, having caused no damage in COX-1(+/+) animals, caused small bowel ulcers in COX-1(-/-) animals. Selective inhibition of COX-1 decreased intestinal PGE(2) levels in COX-2(+/+) and COX-2(-/-) animals by 95%-97%, but caused only small bowel ulcers in the latter group. Dual inhibition of COX-1 and COX-2 in wild-type animals resulted in similar small bowel damage. Between 40% and 50% of untreated COX-2(-/-) animals had increased intestinal permeability and inflammation. Some had ileal ulcers that were distinctively different from indomethacin-induced ulcers. Furthermore, long-term celecoxib administration in wild-type animals was associated with similar damage as in the COX-2(-/-) mice.
  
  
  CONCLUSIONS
  COX-1 deficiency or inhibition and short-term COX-2 inhibition are compatible with normal small intestinal integrity. Dual inhibition of the COX enzymes leads to damage similar to that seen with indomethacin. Long-term COX-2 deficiency or inhibition is associated with significant intestinal pathology despite normal intestinal PGE(2) levels, suggesting a role for COX-2 in the maintenance of small intestinal integrity in the mouse.
authors.affiliation: Department of Medicine, Guy's, King's, St. Thomas' Medical School, London, England.
authors.forename: Gudmundur
authors.initials: G
authors.lastname: Sigthorsson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Simpson
authors.forename: Matthew
authors.initials: M
authors.lastname: Walley
authors.forename: Andrew
authors.initials: A
authors.lastname: Anthony
authors.forename: Russell
authors.initials: R
authors.lastname: Foster
authors.forename: Christoph
authors.initials: C
authors.lastname: Hotz-Behoftsitz
authors.forename: Abbas
authors.initials: A
authors.lastname: Palizban
authors.forename: Joaquim
authors.initials: J
authors.lastname: Pombo
authors.forename: Jo
authors.initials: J
authors.lastname: Watts
authors.forename: Scott G
authors.initials: SG
authors.lastname: Morham
authors.forename: Ingvar
authors.initials: I
authors.lastname: Bjarnason
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004751:Enteritis / Q000139:chemically induced / Q000473:pathology; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000378:metabolism; D007422:Intestines / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D010539:Permeability / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D014456:Ulcer / Q000139:chemically induced
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; C115461:SC 560; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone; D007213:Indomethacin