Role of COX-2 in nonsteroidal anti-inflammatory drug enteropathy in rodents

Abstract

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. Material and methods. We quantified small intestinal damage and prostaglandin E₂ 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. PGE₂ 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.

Key Words::

• Cyclooxygenase
• inflammation and permeability
• NSAID-GI-effects
• PGE₂ (prostaglandin E₂)
• ulcer

Acknowledgements

We thank Molly Jacobs for help with final drafts. All authors declare that the answer to the questions on competing interest are all No and therefore have nothing to declare. Departmental funds were used for the research.

Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.