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Body's First Defense May Be Root of Diseases

Feb 16, 2003
Rob Stein
The Washington Post

Medical researchers are becoming increasingly convinced that the most primitive part of the immune system, usually the body's first defense against infection and injury, may play a crucial role in some of the most devastating afflictions of modern humans , including heart disease, cancer, diabetes and possibly Alzheimer's.

According to a theory that has been steadily gaining ground in recent years, the immune system reaction commonly known as inflammation has a troublesome tendency to go awry. While inflammation's familiar manifestations, such as the redness of an infected cut or a raw sore throat, are unpleasant, the reaction is crucial to survival. It unleashes powerful immune cells, enzymes and other chemicals to fend off viruses, bacteria and other invaders, and to coax wounds to heal.

But inflammation can misfire, or fire far too long, and evidence has been mounting that this "inflammation theory" of disease may cut across what are usually unrelated fields of medicine.

"It's hard now to think of a medical specialty that doesn't concern itself in part with the study of inflammation," said Carl Nathan, chairman of the department of microbiology and immunology at the Weill Medical College of Cornell University in New York. "There's no part of the body that's off limits to the inflammatory response. It can go anywhere -- lung, heart, blood vessels, brain, wherever."

The theory has led to an explosion of research by academic scientists and drug companies to validate the concept and translate it into new ways to prevent and treat illnesses. There is already compelling evidence that some of the damaging effects of inflammation can be countered with common medicines such as aspirin, ibuprofen, cholesterol drugs called statins, and possibly the new generation of "super aspirins" for arthritis such as Vioxx and Celebrex. And scientists are pressing hard to develop entirely new anti-inflammatory compounds.

"It's a major effort. I don't think there are any pharmaceutical companies that don't work on this," Nathan said. Examples are everywhere.

In Kansas City, Mo., Marsha Van Dever is among about 100 women who are lining up to take one of the new arthritis drugs even though they don't have arthritis. The women are, however, at increased risk for breast cancer. They are part of an experiment to see if the painkiller will stave off the malignancy.

In Baltimore, Joel Ingersoll joined a study testing the same drug as a way to prevent or treat prostate cancer.

In Brentwood, Tenn., Bob Green has been gulping down four white capsules every day for three years as part of yet another trial -- this one designed to help see whether the medicine can protect against colon cancer.

And in Boston, researcher Paul M. Ridker has begun gathering thousands of volunteers for a project aimed at producing convincing evidence that a similar approach will save millions of people from an entirely different class of ailments: heart attacks and strokes, the nation's No. 1 killer.

Last month, the American Heart Association and the Centers for Disease Control and Prevention recommended that doctors consider using a test that measures inflammation when trying to decide how to treat patients at risk for cardiovascular disease.

In addition to potentially leading to a new generation of treatments for cancer, heart disease and other ailments, the inflammation theory may help explain why such ills seem to plague modern life.

"Hundreds of millions of years ago, the primary causes of death were infection and starvation. And so the human genome selected for a gene pool with an active immune system . . . because that way you'd have a better chance of surviving," said Ridker at Boston's Brigham and Women's Hospital.

"Fast forward hundreds of thousands of years, and suddenly we're in an environment where infection is not a major threat and food is not scarce. The same genes . . . are now a root cause of the epidemics of diabetes and heart disease."

The strength of the evidence supporting the theory varies depending on the disease, and researchers caution it could still turn out that inflammation plays less of a role than the surge of interest would suggest. But the case is already very strong for heart disease, strong and getting stronger for many cancers, and much more mixed but still tantalizing for illnesses such as Alzheimer's.

While it's clear that inflammation is part of the picture in all these diseases, the trigger for it remains unclear. For heart disease, the spark may be bad cholesterol in the blood or possibly some yet-to-be-identified infection inside artery walls. In cancer, it could be chemical carcinogens such as cigarette smoke, or DNA-damaging compounds called free radicals, or maybe viruses, bacteria or other microbes. In diabetes, part of the problem could be chemical signals sent out by fat cells, some of which are identical to those produced during inflammation.

"I think the first thing we have is an epidemic of unhealthy lifestyle," said Peter Libby, a professor of medicine at Harvard Medical School in Boston. "And the way in which the lifestyle is wreaking its havoc is through inflammation."

Inflammation is part of the earliest defensive system that organisms evolved. It is what causes redness and itchiness where a mosquito bites; heat, pain and swelling when a bowling ball lands on a foot; and sneezing, stuffiness and aches when cold viruses invade. Aspirin, ibuprofen, antihistamines and ice packs alleviate the nasty effects of inflammation, but without it our bodies would be defenseless.

White blood cells, the immune system's scouts, are constantly patrolling, searching for anything dangerous -- a virus, a bacterium, an injury. When they detect something, they rush to the site to attack the threat, and immediately summon help by spewing chemical signals that urgently recruit other, more specialized cells. These cellular SWAT teams can ooze enzymes potent enough to liquefy tissue and bone if necessary to stem a microbial invasion.

"The innate immune cells are the shock troops of immunity designed to respond very quickly," said Gary S. Firestein, chief of rheumatology, allergy and immunology at the University of California at San Diego.

But scientists have long known that the inflammatory response can boomerang. Inflammation run amok is what causes autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and Crohn's disease, which occur when the immune system mistakenly attacks the joints, nerves or digestive system for reasons that remain a mystery.

"It's a hair-trigger kind of design," said Nathan, who edited a special section on inflammation published recently in the journal Nature. "This is a system that has to make a decision in a very short period of time. So you can imagine that sometimes it fires by itself, or sometimes it fires off correctly but doesn't slam shut properly."

The idea that inflammation may be involved in other diseases began to gain credence with the realization that stomach ulcers were caused not by stress, worry or spicy food, but by an inflammation triggered by a bacterial infection. Soon, evidence began to accumulate that inflammation was important in far more than just ulcers.

"If you have a million people engineered for this bear-trap kind of response and put them in a box called life and shake them up and down once in a while, the bear trap will spring when it shouldn't," Nathan said.

The standard theory of cardiovascular disease says cholesterol in the blood accumulates on artery walls, like a pipe getting clogged with gunk. Eventually the passageway gets blocked, usually by a clot, cutting off blood to the heart or brain and causing a heart attack or stroke.

The new theory says that in addition to that process, the immune system can also react to something in the artery, perhaps cholesterol in the blood, devour it and suck it into the artery walls, creating something akin to a pimple. Eventually, the pimple pops, prompting a clot to form, which causes the blockage. That would explain why many people suddenly drop dead from heart attacks even though their arteries look fine.

One of the ways aspirin may protect against hardening of the arteries is by neutralizing substances called prostaglandins, some of the chemical signals sent out during inflammation. A multitude of studies have shown that people who take aspirin and other drugs with anti-inflammatory properties, such as the statin cholesterol drugs, seem to have lower levels of inflammation in their bodies and a lower risk of heart disease.

Ridker's study, known as the Jupiter Trial, will involve 15,000 healthy middle-aged men and women with normal cholesterol to see if the anti-inflammatory properties of statins reduce their risk. "This is the first real test of the hypothesis," Ridker said.

There have been clues for some time about a link between inflammation and cancer. It has long been known that people who suffer from chronic inflammation are at higher risk for cancer. For example, people with ulcerative colitis, a chronic inflammation of the digestive tract, have a higher rate of colorectal cancer.

Part of what inflammation does is promote the growth of cells to heal wounds, and the growth of blood vessels to nourish the wounded area. But evidence has been accumulating that many other forms of cancer may also result from that process gone wild.

"Tumors when they're developing are just proliferating cells. The theory is that it looks much like a wound to the host. So inflammatory cells come in and do their job. They urge the growth onward," said Lisa Coussens, an assistant professor in the department of pathology and the cancer research institute at the University of California at San Francisco.

Scientists have found signs that inflammation may also interfere with normal cell death and produce DNA-damaging free radicals, possibly contributing to cells becoming cancerous in the first place, she said.

Tumors are often teeming with inflammatory cells and their chemical messengers, and genes involved in inflammation are often active -- telltale signs that inflammation is playing a role.

Many studies have found that people who take anti-inflammatory drugs have a lower risk for certain types of cancers, particularly colorectal cancer, as well as precancerous growths. A study led by Robert Sandler of the University of North Carolina at Chapel Hill is expected to be published soon in the New England Journal of Medicine with promising results about the power of aspirin to slash the risk of precancerous growths called polyps in people who have had colon cancer.

Dozens of other studies are underway exploring the potential of using anti-inflammatory drugs to prevent, and possibly treat, a wide range of cancers, including cancer of the breast, bladder, esophagus, skin, prostate and lung.

"There's a tremendous amount of work going on in this field because of the promise of the agents and the convergence of the data, which is quite compelling," said Ernest T. Hawk of the National Cancer Institute.

In Alzheimer's, some scientists think that giving people anti-inflammatory drugs early in life may forestall the development of that devastating brain disease, though that remains highly speculative.

"It may turn out that using the anti-inflammatory drugs in your fifties and sixties may have an impact on what's happening in your seventies and eighties," said Bill Thies, vice president for medical and scientific affairs at the Alzheimer's Association. "People are talking about how you do a trial to test that. This is a piece of science that still evolving."

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