**2. COX and the gastric mucosal barrier**

In 1971, Vane and colleagues first demonstrated that aspirin and other NSAIDs inhibited the synthesis of PGs by blocking COX activity [4]. COX plays pivotal roles in the gastric mucosal barrier [5, 6]. COX catalyzes the conversion of arachidonic acid to the common precursor prostanoids, prostaglandin (PG) H<sup>2</sup> , and PGG<sup>2</sup> . The major PGs produced by the human and rodent gastric mucosa are PGE<sup>2</sup> and PGI<sup>2</sup> , with lesser amounts of PGF<sup>2</sup> and PGD<sup>2</sup> . Each of these metabolites binds to a specific G protein-coupled receptor to trigger intracellular responses. PGs have been shown to accelerate ulcer healing in experimental models and humans [7]. COX exists in two isoforms commonly referred to as COX-1 and COX-2. COX-1 is constitutively expressed in various tissues. In the stomach, prostanoids synthesized via the COX-1 pathway are responsible for cytoprotection of the gastric mucosa and the production of thromboxane by platelets. Although COX-2 is generally expressed at very low levels in healthy tissues, including in the stomach, it is expressed at particularly high levels at sites of inflammation.

It was originally thought that only COX-1 was involved in the gastric mucosal defense system; however, several clinical trials have suggested that a COX-2 selective inhibitor produces lesser, but some, gastrointestinal toxicity compared to traditional NSAIDs [8, 9]. In accordance with this finding, animal studies have suggested that both COX-1 and COX-2 are necessary for gastric mucosal healing, and COX-1 inhibition alone, which can be induced pharmacologically by specific inhibitors or genetically by gene targeting [10], does not cause gastric mucosal injury. It has been shown that a combination of selective COX-1 and COX-2 inhibitors is required to cause hemorrhagic erosion of the gastric mucosa, which is comparable to that observed with indomethacin [11]. Prostanoids produced by COX-2, especially PGE<sup>2</sup> , enhance cell proliferation. The beneficial effects of PGE<sup>2</sup> on gastric ulcer healing in rodents appear to be mediated via the EP4 receptor [12]. In addition, COX-2-derived PG stimulates vascular endothelial growth factor (VEGF) release from gastric fibroblasts, which is an important contributor to ulcer healing [13, 14], likely via stimulation of new blood vessel growth. The increase in COX-2 immunoreactivity that is observed in monocytes, macrophages, fibroblasts, and endothelial cells at the ulcer margin is closely correlated, both temporally and spatially, with the increase in cell proliferation [15]. COX-2 appears to represent a second line of defense that is activated during ulcer healing to compensate for the temporary loss of COX-1 in the mucosa adjacent to the ulcer and assists COX-1 in protecting gastric mucosal integrity. The healing-impairment effect of NSAIDs is also observed with selective COX-2 inhibitors [16].
