Growing evidence suggests inflammation may be at the root of many chronic diseases
February 5, 2003
By Ronald Kotulak
Scientists continue to be amazed at the things aspirin can do, such as lowering the risk of Alzheimer's disease, stroke, heart disease and some cancers. Its newest wonder: greatly reducing the risk of death after open-heart surgery.
How can aspirin do all these things?
To scientists, who not too long ago thought the little pill only relieved pain and thinned blood, aspirin's impressive achievements are providing new clues to understand how the killer diseases of modern society originate and how they might be tamed.
Inflammation was once regarded as the inconsequential aftermath of fighting infections and injuries, but many scientists now believe it may be at the root of heart disease, neurodegenerative disorders, stroke, diabetes and possibly cancer and other chronic diseases.
And it may be that the anti-inflammatory properties of aspirin and other compounds can be used to subdue them.
Infectious diseases were the biggest cause of death until the 1940s and the advent of penicillin. Chronic diseases have since become the major killers, and the recent discovery that the inflammatory process can turn against the body in previously unsuspected ways is helping to explain the source of many of these deadly maladies.
Inflammation is an ancient evolutionary defense against invading organisms that all animals and plants have. In humans, white blood cells engulf germs and spew out toxic chemicals to destroy them. But the chemicals can also destroy nearby healthy tissue, which brings more white cells into battle.
Three things can happen: The immune system wins by destroying germs and repairing tissue; the invading organism wins and the host dies; or neither side wins outright and they settle down to a long, drawn-out battle that results in chronic inflammation.
For millions of years, inflammation only showed its good side, keeping people alive in a sea of germs.
But today, as people live longer, inflammation's dark side has emerged, said Harvard's Dr. Peter Libby, who is also chief of cardiovascular medicine at Brigham and Women's Hospital in Boston.
Scientists are finding that when the immune system's major weapons against bacteria and viruses â€“ toxic chemicals and free radicals â€“ go on an inflammatory spree, they can damage coronary arteries, brain cells and other vital tissues, leading to heart disease and other chronic disorders.
The new information is helping solve a long-standing mystery: Why do half of all heart attacks occur in people who apparently don't have such major risk factors as high cholesterol?
"It's now pretty widely recognized that the whole process of atherosclerosis is a chronic inflammatory disease," said University of Chicago molecular biologist Godfrey Getz.
Scientists are also learning how harmful lifestyles â€“ bad diets, smoking and lack of exercise â€“ can trigger low-grade inflammation inside the body.
Obesity, for example, is potentially dangerous because fat cells release chemical signals that provoke inflammation. Diseases like diabetes arise when an unrelenting inflammatory attack damages the ability of cells to use insulin.
As the rate of obesity among Americans continues to skyrocket, health officials fear a new wave of diabetes, heart attacks and strokes. Heart disease rates in adolescents are already on the rise.
"It's a time bomb," Libby said. "We think that heart disease starts in American teen-agers and will only become manifest many years down the pike."
Old drugs, new uses
Uncovering inflammation's pernicious role in causing disease is spawning new uses for old drugs such as aspirin and other anti-inflammatory agents. It is also fueling research for even more effective compounds to subdue an untamed inflammatory process.
One of these, a family of drugs called statins, is widely prescribed to lower cholesterol, a major risk factor for heart disease and stroke. Scientists now believe that chronic inflammation turns cholesterol into an artery-clogging enemy of the body.
Supporting the link between inflammation and cholesterol is the recent discovery that statins subdue inflammation in blood vessels in a big way. It now appears that the ability of statins to quell inflammation is responsible for the drugs cutting the risk of heart attack and stroke in women and men by one-third.
Statins, in fact, may be even better at taming inflammation than aspirin. The findings have prompted studies to see if statins can also reduce the risk of Alzheimer's disease and multiple sclerosis, a vicious inflammatory attack on nerves. Statin trials may soon start for other inflammatory disorders, including juvenile diabetes and rheumatoid arthritis.
"Statins have almost done for atherosclerosis what antibiotics did for infectious diseases," Getz said. "We hope ultimately to get into the position where instead of having an anti-inflammatory drug that intervenes with inflammation all over the body and produces side effects like bleeding, as in the case of aspirin, we will develop agents that only hit those targets you want."
One of those targets is E-selectin, a chemical alert system in the wall of arteries. When a germ or damaged cholesterol particle infiltrates the lining, it's E-selectin's job to alert the immune system to mount an inflammatory attack to get rid of the intruder.
Dr. John Hallenbeck of the National Institute of Neurological Disorders and Stroke has found a way to use E-selectin in a nasal spray vaccine to protect rats from strokes. The idea is that when E-selectin is administered from outside the body, special white blood cells see it as harmless and signal the immune system not to respond.
So when E-selectin already in artery linings puts out a call for an inflammatory response, immune cells pay no attention and inflammation does not develop.
When rats genetically prone to developing strokes were treated with the nasal spray, they had far fewer strokes than rats not given the spray. The vaccine is expected to be tested early next year in people who already have had a stroke.
Just as the discovery of germs led to tests that could diagnose infectious diseases, scientists are now developing tests to diagnose chronic inflammation, even years before it leads to heart attacks, stroke or possibly Alzheimer's disease.
One of these tests, which costs about $20, measures a chemical signal of inflammation in the blood called C-reactive protein (CRP). Recent studies by Harvard's Dr. Paul Ridker showed that the risk of heart disease increases directly in line with increasing levels of CRP.
Men who have the highest CRP levels have a threefold-increased risk of heart attack and a twofold increased risk of stroke compared with men with the lowest levels. Post-menopausal women with the highest CRP levels are four times more likely to have heart disease than those with the lowest measurements. A higher risk of type 2 diabetes is also linked to elevated CRP levels.
CRP is a more powerful predictor of heart attack and stroke risk than LDL, the notorious bad cholesterol linked to clogged arteries, Ridker found in an eight-year study of nearly 28,000 women.
"It is no longer acceptable for physicians to focus solely on cholesterol since the evidence is overwhelming that those with low cholesterol but high CRP are in fact a very high-risk group," he said. One out of four Americans has elevated CRP levels but normal to low cholesterol levels. Why aspirin helps
Another Ridker study showed why doctors are increasingly recommending that patients at risk for heart disease or stroke take an aspirin every day or every other day: Aspirin therapy provides the greatest protection for people with the highest levels of inflammation.
A recent study in the Archives of Internal Medicine showed that if people took aspirin regularly, their risk of death was reduced by 18 percent. Heart attacks were reduced by 30 percent and strokes by 20 percent.
A New England Journal of Medicine report on more than 5,000 patients undergoing coronary bypass surgery showed that patients given an aspirin shortly after surgery had half the risk of heart attacks and strokes as patients not taking aspirin.
Cardiologists explain that surgery itself triggers a massive inflammatory response that sets the stage for heart attacks, strokes, kidney failure and other complications. Doctors had been reluctant to give aspirin to patients after surgery because of fears it would increase bleeding. But the study showed no increased bleeding from aspirin.
"A lot of the medical community hasn't yet figured out it's inflammation," said Dr. Eric Topol, chief of the Cleveland Clinic Heart Clinic. "There's going to be a sweeping major overhaul in the prevention, diagnosis and management of heart disease."
Another study found that regular doses of aspirin and other nonsteroidal anti-inflammatory drugs (acetaminophen, ibuprofen and naproxen sodium) reduced colon cancer risk by 40 percent to 50 percent. Inflammatory cycle
Dr. Joseph Witztum of University of California San Diego is studying how LDL, or low-density lipoprotein, turns into bad cholesterol with the assistance of the inflammatory response.
When free radicals attack the protein molecules, they become chemically unstable and oxidize. Free radicals can come from such outside sources as cigarette smoke, but most are made internally, primarily from the body's production of energy, and as part of inflammation's killing power.
Once oxidized, LDL takes on the chemical appearance of an infectious germ, Witztum said, which the immune system recognizes as foreign and attacks with inflammation. Stuck in arterial walls, oxidized LDL particles attract macrophages, white blood cells that gobble up the particles.
As the macrophages grow fatter, they turn into foam cells and form pockets in arteries called plaques. The process becomes a vicious cycle: The macrophages spew out free radicals, creating more oxidized LDL, which then recruit more macrophages.
Although the details have yet to be worked out, scientists believe that ongoing inflammation can suddenly rupture a plaque, pouring a cloud of debris into the circulation. The cloud forms a clot, blocking an artery and causing a heart attack or stroke.
In some cases bacterial or viral infections can create similar inflammatory responses, which may explain why people with gum disease are at greater risk for heart disease.
In Alzheimer's disease, scientists believe that an abnormal protein called beta amyloid provokes immune cells in the brain to launch an inflammatory reaction. The protein is stubborn and won't leave, so the inflammation doesn't stop, creating an expanding war zone that claims innocent brain cells as casualties.
Dr. D. Martin Watterson of Northwestern University is developing a new class of synthetic compounds designed to stop the destructive inflammation in the brain.
One member of this family of compounds, called pyridazines, has been able to halt brain inflammation in mice suffering from a disorder that mimics human Alzheimer's disease.
For medical scientists, the new knowledge about inflammation is providing a new understanding of why lifestyle habits can lead to dangerous diseases.
"One of my messages to people and to doctors is you don't necessarily
these problems with pills," said Libby. "You have to start with the
stuff, changing your lifestyle, and then when that's not enough, you
© Copyright 2003 Union-Tribune Publishing Co.