When the U.S. Food and Drug Administration approved the anti-inflammatory drugs Celebrex and Vioxx earlier this year, it marked the start of a new era of custom-designed pain killers that target a specific enzyme. But findings in rats, described in this month's Nature Medicine, suggest to the study's authors that the new drugs may delay the healing of chronically damaged tissue in people. A scientist with Searle, which makes Celebrex, disagrees, arguing that the enzyme inhibitors are a safe and effective treatment for chronic inflammatory conditions, such as rheumatoid arthritis.
Reddish and painful swelling around burns, infected wounds, or chronic irritation are signs that the immune system is attempting to limit damage and spur healing. Aspirin and related drugs exert their soothing effects by blocking cyclooxygenase-1 (COX-1) and COX-2, a pair of related enzymes that catalyze production of inflammatory molecules called prostaglandins. COX-1 is thought to help supply prostaglandins that maintain the stomach lining and salt balance in the kidneys; COX-2 is activated only during injuries and infections. To avoid the side-effects of aspirin such as stomach irritation and ulcers, drug developers over the last few years have designed compounds that block COX-2 alone. But sporadic studies, mainly in animals, have suggested that this tactic can delay healing of ulcers.
Paul Colville-Nash, an inflammation researcher at St. Bartholomew's Hospital in London, and his colleagues wanted to find out whether COX-2 levels decline as inflammation subsides. The team induced inflammation in the lining of rats' lungs, then gave animals either of two COX-2 inhibitors--NS-398, a compound that inhibits only COX-2, or indomethacin, which blocks both cyclooxygenases--or a saline injection. The researchers measured the severity of inflammation and the levels of COX-2 and prostaglandins as the inflammation subsided.
After an early, well-known COX-2 boost, the team found a second, even more prominent peak in COX-2 levels as inflammation waned. What's more, the team noticed a simultaneous rise in a different set of prostaglandins, called PGD2 and PGJ2, that seem to play a role in suppressing inflammation. When they blocked COX-2 activity 2 days after irritating the rats' lungs, the inflammation persisted; by then, the inflammation had already cleared up in control animals. "This suggests that COX-2 also helps the body resolve inflammation," says Colville-Nash.
Experts differ on what the findings might mean for using COX-2 inhibitors to treat people. In rheumatoid arthritis, for instance, bouts of acute inflammation are broken up by periods of remission, during which COX-2 inhibitors might do more harm than good, argues Colville-Nash. James Lefkowith, an immunologist at Searle in Skokie, Illinois, disagrees. "There's no good evidence in humans that COX-2 inhibition has a deleterious role in rheumatoid arthritis," he says. But the study is "clearly interesting," Lefkowith says, because it hints at a possible role in inflammation for the enigmatic PGD2 and PGJ2.