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Study Finds How Aspirin Dampens Inflammation
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Study Finds How Aspirin Dampens Inflammation
When Vioxx, the heavily promoted COX-2 inhibitor, was pulled from the market this month because of its risk of cardiovascular disease and stroke, an entire class of pain relievers came under scrutiny. COX-2 inhibitors were developed as "smart" drugs that would relieve pain and inflammation, but with reduced side effects compared to older--and cheaper--over-the-counter medications.
Charles Serhan and Nan Chiang (below) have discovered that low-dose aspirin may inhibit inflammation as well as clotting. Their findings suggest the mechanism illustrated in the diagram: in platelets, aspirin blocks the COX-1 pathway, which turns arachidonic acid into prostaglandins and thromboxane, a platelet activator. In endothelial cells of blood vessels (right), aspirin acetylates COX-2 instead of blocking it completely, as selective COX-2 inhibitors do. The modified enzyme turns arachidonic acid into the intermediate 15R-HETE, which neutrophils transform into the anti-inflammatory ATL. (Photo by Steve Gilbert)
In a twist to the COX-2 story, a study published Oct. 7 in Proceedings of the National Academy of Sciences shows that aspirin--the age-old, common, and far cheaper standby--may actually outsmart these smart drugs in preventing inflammation. In a clinical trial, a team led by Charles Serhan, the Simon Gelman professor of anesthesia (biochemistry and molecular biology) at HMS, and Nan Chiang, HMS instructor in anesthesia, both at Brigham and Women's Hospital, shows that aspirin triggers a signal that quells inflammation, a previously unknown mechanism in humans. And it does so at low doses, the kind that are known to benefit heart health, but were not thought to control inflammation. "This is the first mechanism documented in vivo of low-dose aspirin's anti-inflammatory action," said Serhan.
Old Drug, New Tricks
Though aspirin is one of our most widely used medications, it still has the potential to surprise. Used to treat pain since the late 1800s, aspirin entered a new phase of interest in the 1950s when it was found to help prevent heart attacks and strokes if taken regularly at very low doses. Aspirin works by targeting both cyclooxygenases, COX-1 and COX-2. According to the standard story, a baby aspirin (81 mg) will act on COX-1 in platelets to prevent blood clotting. This is the dose recommended for long-term heart health. At the dose for adult headaches, aspirin relieves inflammation and pain by inhibiting COX-2 in most tissues. Very high doses are powerful enough to treat rheumatoid arthritis, but can cause excessive bleeding and stomach irritation because of its anticlotting actions. The purpose of designing specific COX-2 inhibitors was to circumvent the anti-clotting side effects of aspirin and other drugs and go straight to pain and inflammation caused by prostaglandins.
| "This is the first mechanism documented in vivo of low-dose aspirin's anti-inflammatory action." |
Aspirin, it turns out, does not completely block COX-2 from functioning. "It doesn't kill the enzyme," said Chiang. "It switches the enzyme's activity from producing pro-inflammatory prostaglandins to making this anti-inflammatory mediator ATL." Normally, COX-2 in the cells lining blood vessels produces molecules that are turned into prostaglandins, lipid signals responsible for inflammation. But aspirin makes a chemical alteration in COX-2, and the enzyme produces a new molecule that is released by the cells and taken up by nearby neutrophils, which then produce ATL. Aspirin is not just blocking inflammation, but actively bringing about its end.
Aspirin Trial Findings
Serhan's group had found evidence for this new mechanism of aspirin in vitro and in animals, but needed human data. They teamed with Paul Ridker, the Eugene Braunwald professor of medicine at BWH, to study samples from a double-blind, placebo-controlled trial of aspirin therapy in 128 healthy adults. Over eight weeks, the subjects received either a placebo or 81-, 325-, or 650-mg daily doses of aspirin. The researchers found that levels of ATL increased significantly in subjects taking the lowest-dose aspirin and only marginally as the dose went up. When compared with thromboxane, which is known to be inhibited by aspirin, ATL levels rose as the amount of the clotting factor diminished.Aspirin was thought to control inflammation only at higher doses, effective in acute situations, but potentially damaging over the long term. The benefits of taking a baby aspirin every day were assumed to stem from the medicine's ability to keep platelets from clumping in blood vessels, thereby helping to prevent clot-related heart attacks and strokes.
It remains to be seen what role ATL production plays in warding off heart disease, but the idea fits well with the recent shift in thinking about inflammation's role in the disease. Conditions like atherosclerosis, heart attacks, and strokes were once thought to be a simple matter of blocked arteries and faulty plumbing, but are now recognized to be a culmination of processes that include chronic inflammation in blood vessels. "Our story says for the first time that low-dose aspirin is likely to be protective against the initial inflammatory events that could lead to deleterious cardiovascular effects," Serhan said.
The study may also help clear up one medical mystery. As Steven Abramson, chair of rheumatology at New York University's Hospital for Joint Diseases, pointed out, "There has been literature suggesting that low-dose aspirin works better than modest-dose aspirin" at protecting the heart. "This is the first potential biological explanation. It may be more than simply inhibiting thrombosis, which would explain the dose dependence." A more long-term study that links ATL levels with outcomes is needed to solidify the connection.
And those carefully designed COX-2 inhibitors? Because they block COX-2 completely, these drugs fail to produce ATL. It is unknown why Vioxx carries cardiovascular risks, but Serhan suspects that shutting off the body's natural protective compounds may play a role. He believes that aspirin can serve as a model for a new kind of drug, one that promotes the body's natural off switches for inflammation, rather than blocking the process from the outset. "These compounds are the body's own endogenous mediators," he said, "and are likely to have fewer unwanted side effects."
--Courtney Humphries