Role of COX-2 in nonsteroidal anti-inflammatory drug enteropathy in rodents.
OBJECTIVE
It is widely thought that cyclooxygenase 1 (COX-1) inhibition with consequential decreases in mucosal prostaglandins, along with concomitant inhibition of COX-2, is pivotal in nonsteroidal anti-inflammatory drug-induced (NSAID) enteropathy. We examined the role of COX-1, COX-2 and topical effects of drugs in NSAID enteropathy.


METHODS
We quantified small intestinal damage and prostaglandin E(2) levels in wild-type, COX-1 and COX-2 deficient mice after administration of R-2-phenylpropionic acid (which has the same topical characteristics as conventional NSAIDs but does not affect the COX enzymes), the conventional NSAIDs flurbiprofen and the selective COX-2 inhibitor celecoxib. We also measured intestinal permeability and inflammation in rats given the selective COX-1 inhibitor SC-560 and NSAIDs. The parameters were assessed at baseline and after administration of the drugs.


RESULTS
R-2-phenylpropionic acid caused small intestinal damage in COX-2(-/-) and wild-type mice given celecoxib, but not in wild type or COX-1(-/-) mice. PGE(2) levels in mice dosed with R-2-phenylpropionic acid were elevated. Indomethacin raised permeability and caused inflammation in rats.


CONCLUSIONS
The combination of COX-2 absence (or inhibition) and the topical effect of NSAIDs lead to changes characteristic of NSAID enteropathy without concomitant COX-1 inhibition and/or associated decreases in mucosal prostaglandins. COX-2 appears to be more important for maintaining small bowel integrity than COX-1.
Hotz-Behofsits
Christoph
C
Department of Medicine, Guy's, King's, St Thomas' Medical School, London, UK. cmhotz@hotmail.com
Simpson
Robert J
RJ
Walley
Matthew
M
Bjarnason
Ingvar T
IT
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D015232:Dinoprostone / Q000378:metabolism; D005480:Flurbiprofen / Q000009:adverse effects; D007249:Inflammation / Q000139:chemically induced*; D007421:Intestine, Small; D008297:Male; D051379:Mice; D011720:Pyrazoles / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000009:adverse effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; C115461:SC 560; D013449:Sulfonamides; D005480:Flurbiprofen; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone