~ Quenching the Flames of Chronic Inflammation

By Dean S. Cunningham, MD, PhD

The flames of a small fire are easy to put out. Once the fire has spread, however, it begins to feed itself . . . destroying everything in its path . . . and becomes extremely difficult to extinguish.

The same is true of chronic inflammation. In its early stages, it can be suppressed using a variety of lifestyle changes, nutrients, and sometimes drugs. Once systemic inflammation takes hold, however, immune cells release dangerous cytokines in a vicious cycle that destroys tissues throughout the body. In response to this tissue destruction, even more inflammatory cytokines (such as interleukin-6) are produced incessantly because the body thinks it is under attack.

Yet even with all the weapons in our armamentarium, we still encounter difficult cases where the production of inflammatory cytokines cannot be suppressed.

Inflammation and Overall Health

When one thinks of inflammation, what usually comes to mind is a local reaction to an injury—for example, an insect bite. In this context, inflammation can be easily visualized as redness or swelling and sensed as pain and heat. Yet as humans age, inflammation more often becomes a stealthy process that causes degenerative disorders such as heart disease, arthritis, diabetes, cancer, and Alzheimer's. Although not apparent, inflammation can smolder like a doused campfire ready to reignite at different sites in the body, or it can rage throughout the body like an uncontrolled brush fire. In either case, however, inflammation can be easily recognized and quantified by laboratory measurement of blood biomarkers such as C-reactive protein.

The measurement of inflammatory biomarkers also can be useful in unmasking an otherwise undetected disease process or determining the efficacy of various anti-inflammatory therapies.

An Inflammatory Condition: Heart Disease

Perhaps the best example of a "nontraditional" inflammatory condition is heart disease.

In the early 1990s, a major paradigm shift occurred in the field of cardiology regarding the pathogenesis of coronary artery disease, atherosclerosis, or hardening of the arteries. Until that time, heart disease was viewed as a rather bland disease, the end result of lipids accumulating and being deposited on the walls of arteries, a process that has its roots in childhood. After identifying the major risk factors for heart disease—elevated cholesterol levels, high blood pressure, diabetes mellitus, tobacco use, obesity, and sedentary lifestyle—researchers realized that these factors accounted for only 50% of the diagnosed cases. What, they wondered, was the basis for, or apparent cause of, heart disease in the remaining 50% of diagnosed cases?

Today, coronary artery disease—the leading cause of death of men and women in the US and western Europe—has been established as a bona-fide inflammatory condition.1 Inflammation damages the cells lining the blood vessels and can cause an acute heart attack by destabilizing arterial plaque (atherosclerosis).

Generating an Inflammatory Response

Inflammation is a highly orchestrated event that involves cells and cell-derived factors, and represents the body's most primitive form of immunity. These cells may consist of monocytes, neutrophils, basophils, eosinophils, or lymphocytes that are transported by the blood to the site of inflammation, or they may be released locally as endothelial cells, mast cells, tissue fibroblasts, or macrophages.

One of the earliest cell-derived factors in the inflammatory response is nuclear factor kappa beta, which is activated in response to oxidative stress, whereupon it up-regulates proinflammatory med-iators. These proinflammatory med-iators include cytokines such as interleukin-6 (IL-6), interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor beta, and interleukin-8 (IL-8). When initiated, they direct the ensuing inflammatory response.

The presence and release of inflammatory proteins are indicators of ongoing inflammation, are of clinical significance, and should not be disregarded. The most widely reported of the inflammatory proteins is C-reactive protein, which may increase in concentration 10,000-fold during acute inflammation. Physiological changes (such as fever and elevated white blood cell count) also are known to accompany inflammation, and are thought to be protective against the inciting stimulus.

Inflammation is thus the first line of defense by which the body's immune system protects against the vagaries of everyday living. Amazingly, these cells and cell-derived factors all work together to preserve health and maintain homeostasis—at least, most of the time. Although the inflammatory response should be self-limited, at times the cells involved and their factors can paradoxically amplify or attenuate the inflammatory response—in effect, establishing a protective response while simultaneously instigating tissue damage. Exactly what tips this important balance one way or the other is unknown, but it is the prolonged release of inflammatory cytokines such as IL-6 that ultimately results in tissue damage.

Biomarkers of Inflammation

C-reactive protein was discovered nearly 75 years ago, so named because it reacts with the pneumococcal C-polysaccharide in patients with pneumonia. High-sensitivity C-reactive protein has become a standard marker in assessing cardiovascular risk and is an even stronger predictor of cardiovascular status than low-density lipoprotein (LDL) cholesterol level. As far back as 1941, Dr. Oswald Avery, who discovered C-reactive protein, suggested that C-reactive protein "closely parallels the clinical course" of disease.

The specificity of C-reactive protein in predicting cardiovascular-related deaths is extraordinarily high. C-reactive protein also is a biomarker for other diseases with an inflammatory component, including colorectal cancer, hypertension, rheumatoid arthritis, sepsis, dementia, diabetes mellitus, and, most recently, metabolic syndrome.

C-reactive protein is produced primarily by the cells of the liver, largely in response to IL-6. In any given individual, C-reactive protein is stable over time, but its levels increase with age, obesity, smoking, and the aforementioned inflammatory conditions. Regardless of the presence or absence of symptoms, an elevated C-reactive protein level is clinically significant and should not be ignored. C-reactive protein levels can be effectively reduced with aspirin,16 statin drugs, exercise, weight loss, insulin sensitizers, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, moderate alcohol intake, and vitamins C and E. C-reactive protein also can be diminished by reducing homocysteine.

IL-6 is a polypeptide product of monocytes and macrophages, and is one of more than 30 members of the interleukin family. IL-6 is the only non-cellular mediator that induces synthesis of all of the liver's inflammatory proteins (most notably, C-reactive protein and fibrinogen). IL-6 is of paramount importance to cardiovascular homeostasis, as it is the principal initiator of the inflammatory response. In addition to monocytes and macrophages, fat cells (or adipocytes) are now known to produce IL-6. Indeed, it has been suggested that overweight and obese individuals or those with metabolic syndrome spontaneously secrete sufficient IL-6 (25% of the total amount secreted) to mimic a low-grade systemic inflammatory disorder, complete with an elevation of inflammatory proteins such as C-reactive protein. IL-6 levels increase with age and have been associated with muscle protein degradation, increased breakdown of fat, and fatigue. Individuals with poor-quality sleep or sleep deprivation also exhibit increased levels of IL-6.

Rheumatoid Arthritis: A Model for Anti-inflammatory Therapy

So, is there a way to combat inflammation in preventing and treating chronic disease? That question has been asked and answered. Rheumatoid arthritis is a chronic inflammatory disease that affects approximately 1% of the population, with women being afflicted three times as frequently as men. The long-term prognosis is poor, resulting in physical disability in over 80% of those affected, and on average reducing longevity by 3-18 years.

In rheumatoid arthritis, IL-6 exhibits many biological actions, including maturation of antibody-producing B cells, activation of T cells, induction of the acute inflammatory response, growth and maturation of cells destined for the bloodstream, and production of cells near the joint itself. Although IL-1, IL-6, and TNF-alpha collectively dictate the nature of the inflammatory response of rheumatoid arthritis, many, if not all, of the observed physical changes are initiated by TNF-alpha. Indeed, it is the imbalance between the protective and destructive components of the inflammatory response that leads to the pathological changes characteristic of rheumatoid arthritis.

The well-known, successful treatment of rheumatoid arthritis with biological therapies—TNF-alpha inhibitors, TNF-alpha monoclonal antibodies, IL-6 receptor monoclonal antibodies, and IL-1 receptor antagonists—has paved the way for development of other biological agents that inhibit inflammatory protein behavior in the treatment of inflammatory disorders. With respect to rheumatoid arthritis, inflammatory protein blockage has been shown not only to reduce significantly the severity of symptoms, but also to slow the progression of joint destruction as determined by serial radiographic studies. Compared to traditionally used corticosteroids, such modulators of the inflammatory response have much greater specificity, are more potent, and have a much more favorable side-effect profile.

Preventing and Treating Cardiovascular Disease

Heart disease may be the next candidate for the anti-inflammatory treatment that has afforded so much relief to patients suffering from rheumatoid arthritis.

Cardiovascular disease is not a local disease, but instead is the manifestation of a systemic disease. Scientists have not ascertained the degree to which certain factors contribute to the duration and severity of inflammation and to the severity of inflammation that occurs in heart disease. These factors include an underlying infection (such as Chlamydia pnemoniae or herpes viruses), direct injury to the blood vessel lining (as caused by cigarette smoke metabolites, reactive oxygen species generated by LDL-cholesterol oxidation, or physical stress from hypertension), and genetic factors. Regardless of the inciting factor, however, inflammatory proteins are released, the purpose of which is the intravascular recruitment of peripheral blood mononuclear cells. These mononuclear cells accumulate at sites of arterial injury and break through the blood vessel lining. This is the central event in the pathogenesis of atherosclerosis, the inhibition of which prevents atherosclerosis in research involving animal models.

After traversing the cell wall, the monocytes take up lipoproteins, thus forming "foam cells," and lay down a fatty streak that ultimately becomes the mature atherosclerotic plaque. The fatty streak is a pure inflammatory lesion consisting only of mononuclear cells and T cells. The fatty streak also acts to perpetuate the inflammatory response. The circulating markers of inflammation such as IL-6, TNF-alpha, C-reactive protein, fibrinogen, and others are highly predictive of future cardiovascular events, and in fact are more predictive than measurement of cholesterol alone.

The endothelial dysfunction of cardiovascular disease may be prevented or improved by pharmacological means (using ACE inhibitors, calcium-channel blockers, and statins) or dietary means (through omega-3 fatty acids, the antioxidant vitamins C and E, folic acid, and L-arginine). While the American Heart Association recommends an LDL-cholesterol level of less than 130 mg/dl to prevent heart disease, it has been shown that 45% of women who sustained a cardiovascular event had an LDL-cholesterol level of less than the recommended 130 mg/dl. One can easily draw the conclusion from this epidemiological study that additional measures beyond traditional pharmacological and current dietary recommendations are needed to adequately protect against heart disease, an inflammatory condition.

Summary and Conclusion

While the cellular and non-cellular communication that occurs in inflammatory responses is similar regardless of the underlying clinical condition, it is not known what goes awry in transforming an intended protective immune response into a pathological response. We do not know whether the immune response itself is too robust or the overproduction of inflammatory mediators is the manifestation of chronic and unrelenting exposure to some stimulus. The importance of the immune response paradox, however, cannot be overemphasized.

Modulation of early-released inflammatory mediators such as IL-6 may permit control of the downstream inflammatory cascade, in much the same way that both statins and aspirin crudely lower C-reactive protein and the resultant risk of a cardiovascular event.

A C-reactive protein blockade may reduce cardiovascular disease, as C-reactive protein serves not only as a biomarker but also as a chemoattractant for monocytes. Novel approaches to the diagnosis and management of cardiovascular and other diseases will lead to earlier detection, improved monitoring, and the development of therapeutic targets.
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