Body's Defender Goes on the Attack

By MARY DUENWALD

t the slightest provocation — a mosquito bite, a mild sunburn, a tiny splinter — the body mounts a hair-trigger defense, sending cells and natural chemicals to destroy dirt or germs and repair the damage. As a result, the site of injury becomes red, swollen, warm and painful — inflamed.

Inflammation happens so frequently that people often do not even notice it. And it occurs not only on the skin, but internally too, when viruses invade the body or the stomach is irritated by spoiled food. It is the body's fundamental way of protecting itself.

In the long run, however, inflammation can harm the very tissues it is meant to heal. Its destructive side has long been evident in diseases like rheumatoid arthritis, in which inflammation cripples the joints, and multiple sclerosis, in which it destroys the insulation surrounding nerve fibers.

But now scientists are coming to realize that inflammation may underlie many other common chronic diseases that come with aging, including atherosclerosis, diabetes, Alzheimer's disease and osteoporosis. Inflammation is also implicated in asthma, cirrhosis of the liver, some bowel disorders, psoriasis, meningitis, cystic fibrosis and even cancer.

"It's beginning to look as if getting old and ultimately wearing down and dying are tied inextricably with the defense mechanism that keeps you alive and in good repair when you're younger," said Dr. Russell Tracy, a professor of pathology and biochemistry at the University of Vermont.

The reason may reach far back into human history, to the hunter-gatherers who lived in peril of infections and injuries. Natural selection would have favored those with a vigorous inflammatory response and few would have lived long enough to suffer the long-term consequences.

"It is possible that the adaptive pattern of an earlier time has resulted in a maladaptive response in our modern environment," said Dr. Paul M. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital in Boston.

By studying inflammation, medical scientists hope ultimately to find new ways of treating a variety of chronic illnesses. What goes on inside the arteries has been a particular area of interest.

For most of the 20th century, doctors thought of blood vessels as a simple network of pipes — a plumbing system that could become clogged by the accumulation of cholesterol. "It was really a hydraulic, nonbiological view," said Dr. Peter Libby, chief of cardiovascular medicine at Brigham and Women's Hospital.

According to this view, if cholesterol deposits grew too large, there would not be enough room left for blood to flow, and the patient would begin to feel chest pains. If a coronary artery became entirely plugged, the person would suffer a heart attack.

But severe blockages, it turns out, cause at most three out of 10 heart attacks. The rest occur in people whose blood is flowing freely, through arteries narrowed by less than half their capacity. These lesser blockages are usually found in people who die of heart attacks relatively young, in their 40's or 50's. For these deaths, doctors needed a new explanation.

Inflammation had been a suspect as early as the mid-1800's, when Dr. Rudolph Virchow, a German pathologist, suggested that injured and inflamed arteries might cause heart attacks. The idea was revived, briefly, in the mid-20th century, but was little noticed as doctors focused on low-fat diets and cholesterol-reducing drugs. The cholesterol therapies were effective — but still, half of all heart attacks and strokes were happening in people with normal cholesterol levels.

By the 1980's, cardiologists were re-examining inflammation. For example, Dr. Libby took cells from the arteries of rabbits and irritated them with a bacterial toxin. Sure enough, the artery cells began releasing proteins called cytokines, which promote inflammation.

Gradually, researchers put together a new narrative for heart attacks and strokes: immune-system cells that cause inflammation burrow into the artery wall and begin gobbling up droplets of fat. These fat- filled cells form a plaque and inflammation thins its fibrous cap. Eventually, the cap ruptures, and the plaque's contents spill into the bloodstream — along with pro-inflammatory cytokines, which encourage clotting. Suddenly, the artery fills with a cloud of rapidly coagulating blood cells. If the cloud is large enough, it forms a clot that blocks the artery and causes a heart attack or stroke.

"This is an idea that has emerged in a popular way in only the last few years," Dr. Libby said. "The blood vessel is a living, breathing organ. And the plaque is not just a graveyard for cholesterol debris; it's teeming with cells."

A primary goal for heart attack prevention, Dr. Libby and others say, should be to keep inflammation to a minimum.

Cardiologists have found a new way to assess a person's risk of atherosclerosis: they measure a substance in the blood called C-reactive protein, a marker of inflammatory activity. Two large studies — one in men and one in women — have demonstrated that the higher a person's C-reactive protein level, the greater the risk of a heart attack or stroke.

Doctors nationwide are adding the C.R.P. test to cholesterol screening to assess people's risk of atherosclerosis. (President Bush had his C- reactive protein level checked in August; it was low.)

"The things that lower C.R.P. levels include diet, exercise and smoking cessation," Dr. Ridker said — strategies long known to cut heart attack risk.

Studies have shown that statin drugs, prescribed to lower cholesterol, can also lower C.R.P. This research raises the tantalizing possibility that statins may be used to prevent heart attacks even in people whose cholesterol levels are normal. But Dr. Ridker cautioned that the evidence was still too preliminary to warrant such use of statins.

He said he hoped soon to launch a nationwide study of statins in people with low cholesterol but high C-reactive protein levels.

Inflammation may also be important in diabetes. Dr. Ridker and others have found that elevated C.R.P. levels are associated with a higher- than-average risk of developing Type 2 diabetes — the kind that occurs in adults.

In diabetes, excess body fat — a major risk factor for the disease — may be part of the inflammatory picture. Fat cells produce cytokines, the proteins that promote inflammation. Studies have shown that people who develop Type 2 diabetes have relatively high levels of these cytokines. Researchers think the cytokines may interfere with the body's ability to use its own insulin, thus bringing on diabetes.

In osteoporosis, the same cytokines seem to accelerate the rate at which bone is broken down. The disease often arises in women after menopause, when estrogen levels drop. Dr. Sundeep Khosla, an endocrinologist at the Mayo Clinic in Rochester, Minn., said estrogen protected against bone loss by decreasing the production of cytokines. When estrogen declines, cytokine levels rise, and bone is lost.

In Alzheimer's disease, inflammation happens in and around the protein deposits — known as amyloid plaques — that accumulate in the brain. For many years, doctors thought that this inflammation was caused by the plaques. But studies have shown that cytokines help create the plaques in the first place.

"Inflammation is directly damaging neurons," said Dr. Paul Aisen, a professor of neurology at Georgetown University Medical Center.

Asthma, too, is an inflammatory disease. Doctors have known this for more than a decade, and commonly prescribe anti-inflammatory steroids to help prevent asthma attacks. Still, as is true for Alzheimer's disease, osteoporosis and diabetes, the exact ways in which inflammation promotes asthma have yet to be worked out.

Inflammation is even believed to be a player in cancer. Tumors spread by commandeering the body's inflammatory mechanisms. Cancer cells dig into neighboring tissue in essentially the same way that inflammatory cells invade the lining of arteries, Dr. Libby said. Inflammation is also involved in angiogenesis, the growth of small blood vessels that support tumors.

Researchers say it is important to find out what causes inflammation to begin with. In asthma, it appears to be airborne allergens like dust mites and cat dander. But in other diseases, the trigger is harder to discern.

In atherosclerosis, many scientists believe that oxidized fat droplets, circulating in the bloodstream, irritate the artery wall. Some suspect certain viruses or bacteria.

Many studies have suggested that some common viral and bacterial infections increase the risk of heart disease. The suspect bugs include Herpes Simplex 1, a virus that causes cold sores; cytomegalovirus, which typically causes no symptoms; the bacteria involved in gum disease; H. pylori, which causes stomach ulcers; and Chlamydia pneumoniae, which causes bronchitis and pneumonia. Chlamydia has been found in many arterial plaques.

Yet it is not clear that any of these infections directly irritate the artery walls. Dr. Tracy and other experts speculate that infections may play only an indirect role, by heightening the body's inflammatory response.

In the same way, Dr. Tracy said, smoking, obesity and arthritis can also crank up inflammation. Obesity promotes inflammation because fat cells produce cytokines. In a recent Italian study, a group of obese women were able to significantly lower their cytokine levels by losing 10 percent of their body fat.

The idea that bacteria are not directly involved in atherosclerosis may explain why studies so far have failed to show that taking antibiotics can reduce a person's risk of heart attacks. But some anti-inflammatory drugs do seem to make a difference.

ACE inhibitors, drugs commonly used to treat high blood pressure, also appear to reduce inflammation. The drugs help prevent heart attacks, strokes and the complications of diabetes, possibly because they block the action of angiotensin, a protein that not only constricts blood vessels but also seems to promote inflammation.

Many other anti-inflammatory drugs exist. The most familiar is aspirin, already taken daily by many people to help prevent second heart attacks. Dr. Ridker's studies show that aspirin works best at preventing heart attacks in people with high C- reactive protein levels.

Scientists are searching for new anti-inflammatory drugs, and also hope to learn why some people seem more susceptible to inflammation than others. Lifestyle almost certainly plays a role, but genes may, too.

"Inflammation in general may provide us with a whole series of new targets for therapy that will treat and prevent diseases in ways we previously had not thought of," Dr. Ridker said. "That makes medical research awfully exciting right now."

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