Running Interference: Fresh approach to fighting inflammation

The more scientists learn about inflammation, the less they like it. Although this bodily process speeds wound healing and corrals microbes, it can also do plenty of harm, as seen in people with arthritis, asthma, and a host of other ailments. Unfortunately, today’s anti-inflammatory drugs pose their own problems. They cause stomach distress in many people, and some drugs seem to hike the risk of heart attacks. So, the search for a safe inflammation fighter goes on.

Bruce D. Hammock, a biochemist at the University of California, Davis, and his colleagues now report that two experimental drugs shield lab mice from extreme inflammation. The findings appear in the July 12 Proceedings of the National Academy of Sciences.

Earlier research had suggested that a troublesome enzyme, called soluble epoxide hydrolase, degrades natural inflammation inhibitors known as epoxyeicosatrienoic acids (EETs). The experimental drugs in the new study bind to and inactivate the enzyme. The study is the first to show that inhibiting the enzyme can benefit an animal, Hammock says.

Hammock and his colleagues first injected mice with molecules from the surface of Escherichia coli bacteria. Although not infective, these molecules provoke a severe inflammatory response.

The mice then received an injection of one of the two enzyme-inhibiting drugs or of an inert substance. Mice getting the drugs survived, whereas within 4 days, plummeting blood pressure had killed all the mice that received placebo shots. Also, mice with unchecked inflammation showed extensive kidney and liver damage.

A flood of inflammatory cells and proteins apparently overwhelmed these mice in a process similar to that caused by blood infection, or sepsis, in people, Hammock says.

The researchers are “controlling the level of EET indirectly by controlling its degradation,” says J. Russell Falck, an organic chemist at the University of Texas–Southwestern in Dallas. “This is a novel approach, and one that’s quite effective,” he says.

“EETs have been largely ignored in medicine,” Hammock says. Instead, drug companies have concentrated on aspirin, ibuprofen, cyclo-oxygenase-2 inhibitors, and other anti-inflammatory drugs that block a single biochemical pathway but don’t protect EETs.

Hammock predicts that the new drugs, which are currently called AUDA-BE and Compound 950, will be tested as oral medicines in people within 18 months.

“We envision these as general anti-inflammatory drugs,” Hammock says. But the new drugs may also counter sepsis, he says.

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