Original ArticlesRole and regulation of cyclooxygenase-2 during inflammation
Section snippets
Basic biochemistry of prostaglandins and their formation
Prostaglandins, the first metabolites of arachidonic acid to be characterized, mediate several key physiologic functions. The formation of prostaglandins begins when arachidonic acid is liberated from phospholipids in the cell membrane by the action of phospholipase A2. At least two separate enzymatic pathways exist for the conversion of arachidonic acid to physiologically important metabolites. In the first, cyclooxygenase (COX) initiates the formation of prostaglandins and thromboxane.
Evidence demonstrating COX-2 selectivity
The issue of COX selectivity of various inhibitors must be defined both in vitro and in vivo, and various experimental systems generate different data. Experimental paradigms may include in vitro cell-free recombinant enzymes, whole-cell preparations, or in vivo models. Investigators at different laboratories may thus produce widely divergent data demonstrating COX-2 selectivity. Further variability is introduced in human studies, in which drugs must be administered at sufficient strengths to
The role of prostaglandins in mediating pain and inflammation
The role of prostaglandins formed by COX-2 in mediating pain, and the inhibitory effects of NSAIDs on this reaction, can be demonstrated in animal models.7 In one such model of acute inflammation and pain, an irritant, carrageenan, is injected into the paw of a rat and paw volume is measured as edema develops.8, 9 In this model, hyperalgesia develops in the injected paw concurrent with the edema. Experimental agents may be evaluated for anti-inflammatory and analgesic activity by administering
Biochemical basis for the distinction between COX-1 and COX-2 and the clinical implications
Although intellectually provocative and medically intriguing, the above discussion does not provide a molecular basis for understanding why some agents and not others demonstrate COX-1/COX-2 selectivity in these model systems. The explanation for the fundamental differences in the structures of the COX isoforms and their roles in the body lay in their respective genes, which occur on two different chromosomes.12
The COX-2 gene contains regions that are characteristic of early response genes and
Conclusions
Cyclooxygenase has been shown to exist in two distinct forms. These isoforms have diverse physiologic and pathophysiologic roles and exhibit pharmacologically important differences in structure and their profiles of inhibition. With the advent of good in vitro assay systems and animal models of pain and inflammation, efforts have turned to the development of potential therapeutic agents that can specifically inhibit COX-2 while sparing COX-1. The in vitro selectivity of investigational agents,
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