The results have applications to arthritis, acne, atherosclerosis, and aging

By William J. Cromie

Gazette Staff

Discoveries about how inflammation works in the body are leading to new compounds for treating diseases ranging from acne and arthritis to atherosclerosis. The new information has also uncovered fascinating connections between inflammation and cholesterol.

Researchers at the Medical School identified compounds in our bodies that naturally prevent destructive inflammation, such as occurs in rheumatoid arthritis and tissue injuries during surgery. These compounds, so new they don't have easy-to-pronounce names, are known as polyisoprenyl phosphates; the researchers are focusing on one in particular, called PSDP.

"From the structure of PSDP, it should be possible to develop new drugs to treat inflammatory responses due to injury or disease," says Charles Serhan, professor of anaesthesia. "This same compound is involved in the formation of cholesterol, and so provides the first evidence for a link between the generation of inflammation and the making of a molecule tied to cardiovascular disease."

Low density or "bad" cholesterol increases the production by blood cells of damaging molecules known as free radicals, which can lead to clogged arteries. This link raises questions about the impact of cholesterol-lowering drugs on the body's immune system, which protects it from disease. Do the drugs have a beneficial side effect, and does this provide a route to developing better drugs to lower cholesterol?

Working with colleagues at Brigham and Women's Hospital, Serhan found that PSDP inhibits inflammation by blocking production of free radicals derived from ordinary oxygen. These highly reactive molecules are thought to play a role in both atherosclerosis and aging.

In addition to PSDP, Serhan's team has found a natural compound, triggered by taking aspirin, which he thinks can be used to treat problems such as psoriasis and acne. The compound, and newly designed ones similar to it, offer the potential of being better than aspirin and of lacking such negative effects as stomach irritation and bleeding.

The Good, Bad, and Inflamed

These promising compounds emerge from basic research on

the good and bad done by white blood cells of the immune system. When a bacteria, virus, or other dangerous foreigner invades the body, the immune system dispatches these soldier cells to the point of attack. White cells known as neutrophils engulf the invaders and release potent oxygen radicals to destroy them.

In various circumstances, large numbers of white cells accumulate and become overactive. Dangerous radicals escape from the cells and destroy healthy tissues. Over a long time, such inflammation produces problems like rheumatoid arthritis and, perhaps, atherosclerosis, or hardening of the arteries. Over a short time, surges of reactive oxygen damage organs during surgery.

Rheumatoid arthritis and atherosclerosis take decades to develop. Some surgical procedures, however, produce the same effect in minutes. For example, an artery clamped off for surgery mimics one closed by plaque deposits. When a surgeon opens the clamp, the sudden gush of blood includes active white blood cells that release destructive molecules.

Serhan and his colleagues study such reperfusion injuries to isolate compounds that naturally limit this destruction and to determine how they work. Their major targets are proteins responsible for converting harmless oxygen into inflaming radicals. After years of work, they discovered a small compound in the surface of white blood cells that inhibits such activity.

Serhan, along with Bruce Levy and Nicos Petasis, broke the molecule down to determine its structure, a necessary first step in building a drug that would do the same thing.

"At this point, something completely unexpected happened," Serhan recalls. "PSDP turned out to be involved in the making of cholesterol."

When teasing apart the workings of molecules, it's startling to find a compound active in both protection against disease and in the manufacture of a substance like cholesterol, which has a major role in the formation of hormones in our bodies.

"We have already begun to make and test compounds that might be used to regulate inflammation and cholesterol," Serhan says. "One goal is to make a drug against both inflammation and surgically induced injuries which would not raise cholesterol levels. We also need to investigate how cholesterol-lowering drugs impact a person's immune defenses."

More fundamental and far-reaching is their discovery of a class of compounds that carries out two different basic tasks. "This class of compounds, we believe, extends to other biological systems, and determining what these are should give us a deeper understanding of how the human body works," Serhan notes.

Building A Better Aspirin

Serhan's lab also works on making and testing a compound that promises new treatments for skin inflammations and atherosclerosis. Acting on the premise that hardening of the arteries is a response to inflammation, the scientists did experiments in which they placed white blood cells in contact with blood-vessel linings. They did this in the presence and absence of aspirin.

Four years of such experiments led to finding a new way in which aspirin inhibits prostaglandins, hormone-like chemicals responsible for inflammation, pain, fever, and blood clotting. Prostaglandins probably account, at least in part, for aspirin's role in preventing both inflammation and atherosclerosis.

Once they defined the structures of key substances, they could make them in the laboratory. "We were able to identify and make a molecule that is like the body's own answer to aspirin," Serhan says.

Unfortunately no one could think of an easy name like aspirin; the researchers call it 15-epi-lipoxin A4.

Despite its name, the molecule might lead to a new class of anti-inflammatory drugs superior to aspirin. Once in the bloodstream, aspirin goes everywhere, including the stomach. Drugs made to function more like natural inflammation-fighters would work selectively on white blood cells and not produce negative effects like stomach bleeding.

Serhan and Levy are testing the aspirin compound on mice, applying it like a salve to inflamed areas of their ears. Preliminary results hint at the possibility of making drugs that might alleviate human skin problems like psoriasis and acne.

At another level, studying such compounds can lead to a better understanding of aspirin's role in preventing or slowing atherosclerosis. Since PSDP compounds act on free radicals, which also have been implicated in this major malady, the two research efforts merge at this point.

"We now have two different sets of compounds," Serhan says. "The aspirin-triggered compounds working outside cells to prevent inflammation, and PSDP-like compounds working inside white cells to prevent the generation of destructive oxygen molecules. They clearly must have an impact on each other, but we don't yet know the details."

There is another aspect of this research that could lead to major consequences for human biology. Those fearsome oxygen radicals also seem to be agents of aging. Might not anything that regulates them also play a role in slowing aging?

That, says Serhan, "would be beyond my wildest dreams."