Inflammation: A unifying theory of disease?

Chronic inflammation plays an important role in the development of many diseases.

Although there may never be such a single path, mounting evidence suggests a common underlying cause of major degenerative diseases. The four horsemen of the medical apocalypse — coronary artery disease, diabetes, cancer, and Alzheimer's — may be riding the same steed: inflammation.

Research on inflammation has created a shift in medical thinking. For two millennia it has been viewed mainly as a necessary, even beneficial, response to illness or injury. But for many people persistent can be the most significant causative factor in many diseases.

What is inflammation?

Inflammation is part of the immune response. It's a process that depends both on the physical actions of white blood cells and the chemicals that they produce: antibodies, cytokines, and the like. Over the last several decades, scientists have identified dozens of new immunological and inflammatory molecules and the pathways through which they interact. The loops and feedbacks of those pathways mean inflammation can be turned on and off in any number of ways. The problem comes when it is left on, for no apparent reason.

For simplicity's sake, immunologists still describe inflammation as dependent on two basic processes. The first, innate immunity, relies on granulocytes and complement. Granulocytes are short-lived white blood cells containing enzyme-filled granules that dissolve foreign substances. Complement is an array of circulating proteins produced in a cascade of enzymatic activity in the presence of microbes.

The second process, adaptive immunity, is directed specifically at microbes that have invaded the body previously. It's largely the responsibility of white blood cells called lymphocytes. T lymphocytes, or T cells, are the master strategists of the process, directing cells and chemicals to eradicate the invader. B lymphocytes, or B cells, produce antibodies, which attach to specific pathogens and call in the complement to help dispatch the invader. Macrophages (literally "big eaters") are the scavengers, swooping in to eliminate the remains of microbes, dead granulocytes, and cellular debris created in the skirmish. While they clean up, macrophages also process information about individual pathogens and transmit it to the lymphocytes, which store the information for future reference.

As pathogens are eliminated, suppressor T cells turn down the inflammatory response, so the regeneration of tissue injured either by the invader or by "friendly fire" from the immune system can begin. Fibroblasts, cells that produce collagen and fibrin, arrive to create a scaffold for new tissue cells. If the damage is extensive, fibrin and collagen may become thick enough to replace the original tissue and form a scar.

Chronic inflammation

The first-century Roman physician Aurelius Cornelius Celsus described the four cardinal signs of inflammation — calor (heat), dolor (pain), rubor (redness), and tumor (swelling) — a Latin litany still learned by medical students today. But these symptoms are mainly tip-offs for acute inflammation.

Chronic inflammation often stays under the patient's — and doctor's — radar. It occurs when the triggering agent isn't entirely eliminated or the suppressor T cells don't call off the immune system after the body has repulsed the invasion.

All of us adults have some level of chronic inflammation slowly waging a war of attrition on tissues and organs, its activity often evidenced only in blood tests. But if it's turned up a notch or two, chronic inflammation can wear away at the body so that the damage is devastating.

Coronary artery disease

Cardiovascular research indicates that inflammation acts in concert with an excess of "bad" LDL cholesterol to create atherosclerosis. At high blood levels, LDL cholesterol becomes oxidized. That makes it recognizable to the immune system and marks it for ingestion by macrophages. The lipid-loaded macrophages trigger complement activity that damages the vascular endothelium — the layer of cells that lines the inside of blood vessels. Macrophages and their fatty cargo slip through the resulting cracks and lodge next to the arterial wall, where they are encased in a shell of fibrin and form arterial plaque. As the plaque grows and its fibrin coat is stressed, it may rupture, forming a clot that blocks a coronary artery supplying oxygen to the heart muscle. Heart tissue nourished by the artery then dies, causing a heart attack.

Studies have determined that people whose blood level of C-reactive protein (CRP), a marker of inflammation, rank in the top third are twice as likely to have a heart attack as those with CRPs in the lowest third. The risk is even greater if a person also has high cholesterol.

Diabetes

Some large observational studies have shown that people with high levels of CRP are more likely to develop insulin resistance, a precursor to full-fledged diabetes in which cells rebuff insulin and therefore don't properly metabolize glucose circulating in the blood.

Cancer

Nearly 150 years ago, the pathologist Rudolf Virchow termed cancer a "wound that doesn't heal." He noticed that tissue from malignant tumors contained high concentrations of inflammatory cells and hypothesized that the tumors often formed at sites of chronic inflammation. Recent evidence suggests that he was right. About 15% of cancers — including cancers of the liver, cervix, and stomach — are closely linked to infectious diseases. Cigarette smoke and asbestos contain inflammatory substances. Exposure to cigarette smoke is a notorious cause of lung cancer, and exposure to asbestos is linked to mesothelioma, a cancer of the tissue lining the chest.

Moreover, laboratory research has shown that products of inflammatory reactions, such as reactive oxygen species, damage cellular DNA, creating mutant genes that lead to cancer. Macrophages, the mop-up molecules in the inflammatory process, churn out numerous tumor growth factors and appear to spur on angiogenesis, the growth of new blood vessels that nurture tumor cells with a fresh supply of blood. In short, malignant tissues seem to commandeer many of the inflammatory weapons sent out to vanquish them.

Alzheimer's disease

Doctors once thought the central nervous system was outside the reach of the immune system. The blood/brain barrier, formed by tightened capillaries, acts like a bouncer, screening out inflammatory cells and molecules so they can't enter the brain. But the brain appears to have its own branch of the immune system. Cells inside the brain called microglia, the counterparts to macrophages, swarm and engulf foreign substances and release inflammatory molecules. Excess production of a molecule called beta-amyloid appears to play an important role in Alzheimer's disease, but the immune response may also be involved. Once microglia ingest beta-amyloid, they become enshrouded in fibrin and form the plaques characteristic of the disease.

Preventing inflammation

Commonsense health practices remain the most important ways to dampen inflammation:

• Staying physically active throughout the day and scheduling time for aerobic exercise and resistance training sessions
• Eat a Mediterranean style diet that emphasizes fruits, vegetables and healthy oils, instead of processed foods and products high in saturated fats
• Maintain a healthy weight
• Avoid tobacco products and other toxins
• If you drink alcohol, limit it to an average of one drink per day

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