Up‐regulation of COX‐2 by inhibition of COX‐1 in the rat: a key to NSAID‐induced gastric injury

Abstract

Background: A recent study demonstrated that inhibition of both cyclooxygenase (COX)‐1 and COX‐2 is required for the development of nonsteroidal anti‐inflammatory drug (NSAID)‐induced gastric lesions. However, the role of COX‐1 or COX‐2 inhibition in the pathogenisis of these lesions remains unclear. Aim: To examine the gastric ulcerogenic properties of selective COX‐1 and COX‐2 inhibitors in rats and to investigate further the relationship of COX inhibition to various events involved in the process of NSAID‐induced gastric lesions. Methods: Animals were given various COX inhibitors p.o., either alone or in combination, and killed 8 h later. Under the treatment, gastric damage, prostaglandin (PG) E2 content, mucosal permeability, myeloperoxidase (MPO) activity as well as gastric motility were examined. Results: The nonselective COX inhibitor indomethacin inhibited PGE2 production, enhanced gastric motility, and provoked severe lesions in the stomach, with an increase in mucosal permeability and MPO activity. In contrast, the selective COX‐2 inhibitor rofecoxib did not induce any damage in the stomach and had no effect on mucosal PGE2 content. Similarly, the selective COX‐1 inhibitor SC‐560 also caused no gastric damage, despite inhibiting PGE2 production. The combined administration of SC‐560 and rofecoxib, however, provoked gross damage in the gastric mucosa, in a dose‐dependent manner for each drug. SC‐560, but not rofecoxib, caused marked gastric hypermotility and an increase in mucosal permeability, although an increase in MPO activity was observed only when rofecoxib was coadministered. The normal gastric mucosa expressed COX‐1 mRNA and not COX‐2 mRNA, but COX‐2 mRNA was expressed in the stomach after administration of SC‐560 as well as indomethacin but not rofecoxib. Conclusion: These results suggest that the gastric ulcerogenic properties of NSAIDs are not accounted for solely by COX‐1 inhibition, but require the inhibition of both COX‐1 and COX‐2. The inhibition of COX‐1 up‐ regulates COX‐2 expression, and COX‐2/PGs may, in turn, counteract the deleterious affects of gastric hypermotility due to COX‐1 inhibition.

New Therapeutic Strategy for Amino Acid Medicine: Prophylactic and Healing Promoting Effect of Monosodium Glutamate Against NSAID-Induced Enteropathy

“…Loxoprofen (10 -60 mg/kg), administered orally to fed rats, dose-dependently produced multiple hemorrhagic lesions in the small intestine 24 h later, mainly in the jejunum and ileum, similar to other conventional NSAIDs, and the severity of the lesions generated by loxoprofen at 60 mg/kg was almost equivalent to that caused by indomethacin at 10 mg/kg (10,11). Following the administration of loxoprofen at 60 mg/kg, the level of prostaglandin (PG) E 2 in the intestinal mucosa significantly decreased 2 h later, the effect persisting for about 24 h (9).…”

Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum?

“…But maybe acetaminophen targets an additional enzyme. We know there may be both redundancy and compensatory increases in COX enzymes; for instance, COX-2 may be upregulated when COX-1 is inhibited in the stomach (32). Furthermore, Dan Simmon's group has previously proposed the existence of an isoform of COX-2 that is particularly sensitive to acetaminophen (33,34).…”

Lafutidine Protects the NSAID-Induced Small Intestinal Lesions Mediated by Capsaicin-Sensitive Afferent Neurons

“…Since mucus plays an important part in the innate host defense against intestinal pathogens and irritants, it is possible that a decreased mucus production/ secretion plays a role in the pathogenic mechanism of NSAID-induced intestinal damage by accelerating bacterial invasion in the mucosa. We have previously reported that indomethacin at an ulcerogenic dose reduced the amount of mucus secreted in the small intestine, in a PGE 2 -sensitive manner, and this effect preceded bacterial invasion [10]. Lafutidine increased mucus secretion in the stomach, at least partly mediated by capsaicin-sensitive sensory neurons [28,29].…”

“…Several factors such as intestinal hypermotility, enterobacteria, neutrophils, nitric oxide (NO), and inducible NO synthase (iNOS) are involved in the pathogenesis of these intestinal lesions [3][4][5][6][7], yet a deficiency of endogenous prostaglandins (PGs) due to cyclooxygenase (COX) inhibition is most important in the background for the intestinal ulcerogenic response to NSAIDs [8][9][10]. Recent clinical studies, using capsule endoscopes or double-balloon endoscopes, confirmed that NSAIDs damage the small intestine in patients at a higher incidence than previously thought.…”