Selected Clinical Examples of Tissue Repair and Fibrosis

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Aspirin: An Old Actor with a New Role

Rubor (erythema), tumor (swelling), calor (warmth), and dolor (pain) have long been recognized as classic elements of inflammation. These are active features driven by a host of mediators that affect the behavior of blood vessels, inflammatory cells, and nerves. In particular, metabolites of arachidonic acid such as the prostaglandins and leukotrienes play important roles. Consequently, drugs that target the phospholipase-mediated release of arachidonic acid precursors (e.g., glucocorticoids) or the production of prostaglandins (e.g., cyclooxygenase [COX] inhibitors, such as aspirin) have a salubrious effect on inflammation. These drugs, however, are not without side effects. Fortunately, several new targets are in the therapeutic cross-hairs thanks to an improved understanding of the normal pathways by which inflammation is intrinsically modulated. Until recently, the natural resolution of inflammation was considered a passive process; the prevailing view was that once the inciting stimulus was removed by the inflammatory response, the signals driving the activity just progressively fizzled out. It is now clear, however, that the pathways triggered early in inflammation also set into motion the production of mediators that ultimately actively shut down inflammation. Thus, arachidonate precursors that can give rise to pro-inflammatory leukotrienes via the action of 5-lipoxygenasealso can be converted to anti-inflammatory lipoxins through the subsequent activity of 12-lipoxygenase. Somewhat counterintuitively, then, upstream inhibition of the 5-lipoxygenase enzyme can actually prolong and augment inflammation by removing the substrate for a later enzyme that actively promotes resolution. Still other natural anti-inflammatory compoundscalled resolvins and protectinsare generated from omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Found in superabundance in cold-water fish, these essential polyunsaturated fatty acids have long been associated with beneficial effects in atherosclerosis, asthma, and cancer. When EPA and DHA are sequentially modified by cytochrome P-450 and lipoxygenase enzymes, they form potent anti-inflammatory products that block neutrophil and monocyte recruitment and mediator production. A number of the resolvins also are impressively analgesic, interfering with both peripheral and central pain pathways. Consequently, several resolvin analogues are in clinical trials; although they show clinical promise, their availability is several years away. Fortuitously, aspirin, an over-the-counter drug that augments resolvin production, is already on hand. The well-described mechanism of action for aspirin is the irreversible acetylation of COX proteins. Although this prevents the production of the pro-inflammatory prostaglandins, the acetylated protein can be the first enzymatic step in producing resolvins! Thus, aspirin is not only anti-inflammatory but also pro-resolving; the other NSAIDs, which merely block (but do not acetylate) COX, do not have this effect. It is more than ironic that one of the oldest (and cheapest) of drugs may be at the cutting edge of the future of antiinflammatory agents.