Chronic Inflammation: The Cause of Disease?

Chronic inflammation is one of the hottest topics in the medical community these days. While inflammation’s healing properties have long been known, studies suggest that inflammation also is a main cause of chronic illness. Some believe that chronic inflammation may be a “unified field” explanation of disease — one that ties together the phenomena for the cause of all illnesses — that eventually may lead to a new and simpler way of warding off disease. As such, the link between inflammation and chronic illness is being studied in the areas of cardiology, neurology, immunology, obesity and cancer. The quest is for a deeper understanding of how inflammation works and the role it plays in some of the most chronic and, often, deadliest diseases of the 21st century.

The Role of Inflammation

Inflammation, also known as an inflammatory response, is one of the ways the immune system responds to antigens that cause disease. The immune system produces disease-fighting chemicals (histamine, macrophages and cytokines) to fight off antigens, which results in redness, swelling and pain. This type of inflammation, known as acute inflammation, typically ends when the antigens are destroyed. But, it is now known that in some cases, the body continues to produce disease-fighting chemicals in the absence of antigens, resulting in chronic inflammation.¹

Chronic inflammation, also known as low-grade or systemic inflammation, plays a puzzling and long-lasting role in the body. In essence, the body attacks its own healthy tissues and organs; it becomes a victim of its own success. “We evolved as a species because of our ability to fight off microbial invaders,” explains Dr. Peter Libby, chief of cardiovascular medicine at Brigham and Women’s Hospital at Harvard Medical School in Boston. “The strategies our bodies used for survival were important in a time when we didn’t have processing plants to purify our water, when we didn’t have sewers to protect us.” But this evolutionary perspective is changing now that people are living longer and our lifestyles have so dramatically changed.²

Measuring Inflammation in the Body

While there are many signs of an inflammatory response, clinically the most common tests to diagnose inflammation include measuring erythrocyte sedimentation rate, white blood count and albumin levels, all of which are high markers of inflammation. However, all of these tests could show an abnormal result that may be a cause of a condition unrelated to inflammation.

Various cytokines and adhesion molecules also can be measures of inflammation. They are not often used in clinical settings because they don’t identify the source of the inflammation within the body. But, they often are used in basic scientific studies to investigate the cellular and molecular processes involved in the pathogenesis of inflammation-related disease.

The prototypic clinical biomarker of cardiac-related inflammation and a general marker of inflammation is C-reactive protein (CRP), an acute-phase reactant protein synthesized in the liver. Because cardiovascular disease is now thought to be caused by inflammation, those individuals who have already had a heart attack can be given a highly sensitive CRP, or hs-CRP, test.3 Even so, a CRP test is not routine as there is no certainty about what an individual’s CRP level should be.⁴

Chronic Inflammation as a Cause of Chronic Diseases

One question is whether inflammation actually causes chronic diseases or merely accompanies them. And while the jury is out yet, the connection between the two can’t be overlooked.

Poor lifestyle habits such as obesity, high blood pressure, unhealthy cholesterol levels, smoking, etc., are believed to have a great effect on how the body’s immune system can spiral out of control.⁵ Other likely causes of chronic inflammation include those from agents that persist for a long period of time, including microbial infections, environmental antigens, autoimmune reactions or persistent activation of inflammatory molecules.³

While the effects of chronic inflammation vary widely depending on where the inflammation occurs, more and more research suggests that chronic inflammation could be at the root of a host of diseases. And, the link between chronic inflammation and disease is changing the way many scientists conduct research. Several years ago, researchers went about their own fields of study; today, cardiologists, rheumatologists, oncologists, allergists and neurologists across the world are all talking to one another because they are realizing that they are all studying the same thing: inflammation. Below are some of the diseases currently under study.

Heart disease. Dr. Paul Ridker, a cardiologist at Brigham and Women’s Hospital, was the first to study the link between inflammation and bursting plaques that result in heart attacks. In the 1990s, using an hs-CRP test, Dr. Ridker looked at low levels of CRP (less than 10 mg/L) that are found in otherwise healthy people and that indicated only a slightly elevated inflammation level. By 1997, Dr. Ridker and his colleagues had shown that healthy middle-aged men with the highest CRP levels were three times as likely to suffer a heart attack in the next six years as were those with the lowest CRP levels.

Inflammation experts eventually determined that having a CRP reading of 3.0 mg/L or higher triples the risk of heart disease, and the danger is even greater in women. By contrast, those with extremely low levels of CRP, less than 0.5 mg/L, rarely have heart attacks. The theory is that as the level of LDL cholesterol increases in the blood, some of it seeps into the lining of the coronary arteries and gets stuck there. When the macrophages come in to try to clean out the cholesterol, for some reason, the cytokine signals increase the inflammatory process instead of decreasing it, and the plaque becomes unstable. “This is not about replacing cholesterol as a risk factor,” says Dr. Ridker.

“Cholesterol deposits, high blood pressure, smoking — all contribute to the development of underlying plaques. What inflammation seems to contribute is the propensity of those plaques to rupture and cause a heart attack. If there is only inflammation but no underlying heart disease, then there is no problem.”

While cardiologists still don’t recommend that the general population be screened for inflammation levels, there is a general consensus that CRP should be measured in those with a moderately elevated risk of developing cardiovascular disease.²

More recently, an international consortium of more than 170 researchers conducted a massive meta-analysis that pooled genetic data from more than 190,000 research participants to provide insights into the molecular pathways causing the plaque buildup seen in coronary artery disease. They identified 15 new genetic regions that may be linked to heart disease, bringing the number of genetic links to heart disease found through genome-wide association studies to 46. Twenty-five percent of those genetic regions were strongly linked to cholesterol, especially high levels of low-density lipoprotein (bad cholesterol), and 10 percent were linked to high blood pressure. But, according to Themistocles Assimes, an assistant professor of medicine at Stanford University, “Perhaps the most interesting results of this study show that some people may be born with a predisposition to the development of coronary atherosclerosis because they have inherited mutations in some key genes related to inflammation. There has been much debate as to whether inflammation seen in plaque buildup in heart vessels is a cause or a consequence of the plaques themselves. Our network analysis of the top approximately 240 genetic signals in this study seems to provide evidence that genetic defects in some pathways related to inflammation are a cause.”⁶

Arthritis. Chronic inflammation is the hallmark of autoimmune disorders such as arthritis, multiple sclerosis and lupus. But what causes this inflammation remains a puzzle. A team of researchers from Brigham and Women’s Hospital and Merck Frosst Centre for Therapeutic Research in Quebec studied the role of leukotriene B4 (LTB4) in leukocyte recruitment and inflammation in inflamed arthritic joints. They found, among other things, that levels of LTB4 were significantly elevated in the joint tissues of mice with chronic arthritis, whereas there were no leukotrienes detected in the joint tissues of mice without arthritis. In addition, they found that increasing concentrations of LTB4 correlated strongly with increasing arthritis severity while the disease was becoming established.⁷

Diabetes. Diabetes was first treated with high doses of salicylates, a group of aspirin-like compounds, which worked to reduce sugar levels but also caused side effects such as a constant ringing in the ears, headaches and dizziness. Fortunately, insulin was isolated in the 1920s as a treatment for diabetes. But in the past few years, researchers are once again looking at the salicylate approach, and they have found that diabetes is a complex interplay between inflammation, insulin and fat (either in the diet or in large folds under the skin). In a study conducted at the Joslin Diabetes Center in Boston, a strain of mice bred with fat cells that were “supercharged inflammation factories” became less efficient at using insulin and went on to develop diabetes. “We can reproduce the whole syndrome just by inciting inflammation,” says Steve Shoelson, a senior investigator. The results suggest that a well-timed intervention in the inflammatory process might reverse some of the effects of diabetes.²

There also is research to suggest that high CRP levels may indicate a greater risk of diabetes. Epidemiologic studies have demonstrated a positive association between CRP level and diabetes mellitus in U.S. race ethnicities. One specific study, however, examined the association between high-sensitivity CRP level and diabetes mellitus in a representative sample of U.S. non-Hispanic blacks. Among the 1,479 participants ages 20 years and older, higher CRP levels were positively associated with diabetes mellitus, independent of smoking, waist circumference, hypertension and other confounders. In addition, the association persisted in separate analyses among men and women, and the results were consistent in subgroup analyses by categories of age, smoking, body mass index and hypertension status. According to the researchers, inflammatory processes previously shown to be related to diabetes mellitus in other race ethnicities may be involved in non-Hispanic blacks also.⁸

Alzheimer’s. In 1997, neurologists presented research that showed people who had been regularly taking anti-inflammatory medicine like ibuprofen had much lower rates of Alzheimer’s disease. Then, in 2001, a study showed an 80 percent reduction in risk of Alzheimer’s among those taking anti-inflammatory medicines daily for two years. According to Linda Van Eldik, a neurobiologist at Northwestern University School of Medicine, whenever the brain is injured or irritated, glial cells pump out cytokines, chemical signals to begin the inflammatory process. But “in chronic neurogenerative diseases like Alzheimer’s, these glial cells are activated too high or too long or both.”⁹

A study reported on in 2005 supported the conclusion that neuroinflammation is associated with Alzheimer’s disease. In the study, both the microglia (the immune cell of the brain) and astrocytes (glial cells of the brain) were shown to generate beta-amyloid protein (Abeta), one of the main pathologic features of Alzheimer’s. Abeta has been shown to act as a pro-inflammatory agent causing the activation of many of the inflammatory components.10

Cancer. For the past three decades, researchers at the Massachusetts Institute of Technology (MIT) have been studying chronic inflammation of the liver, stomach or colon as a risk factor for cancer of those organs. In their most recent study, the researchers looked at how a bacterium called Helicobacter hepaticus (H. hepaticus) alters genes and chemicals in the liver and colon. After examining mice with H. hepaticus, they found that after 10 weeks, the mice developed severe colitis and hepatitis, and at 20 weeks, some also had developed colon cancer. They also examined the tissue damage in the mice over the course of those 20 weeks to assess damage to DNA, RNA and proteins. They found that levels of one of the damaged products in DNA and RNA, chlorocytosine, correlated well with the severity of the inflammation, which they determined could serve as a marker to predict the risk of chronic inflammation in patients with infection in the colon, liver or stomach.

The researchers also noticed that the liver responded differently than the colon. When the DNA of healthy tissue comes under attack, it triggers a mechanism that attempts to repair the DNA, but that repair was more active in the liver than in the colon, even though both experienced DNA damage. What’s more is that in the colon, but not the liver, neutrophils released hypochlorous acid (a constituent of household bleach). The acid causes significant damage to molecules like DNA, RNA and proteins by attaching a chlorine atom, which is an effective way to kill bacteria, but it can cause similar damage to the epithelial cells in the lining of the colon if the acid leads into surrounding tissue. “It’s possible that we have kind of a double whammy [in the colon],” says Peter Dedon, a professor of biological engineering at MIT. “You have this bacterium that suppresses DNA repair, at the same time you have all this DNA damage happening in the tissue as a result of the immune response to the bacterium.”¹¹

Many studies are looking into the possibility that mutation and inflammation are mutually reinforcing processes that can transform normal cells into potentially deadly tumors. For instance, it is known that macrophages and other inflammatory cells produce oxygen-free radicals to destroy anything that crosses their path, particularly DNA. But if the oxygen-free radicals damage rather than destroy a cell, it could lead to a genetic mutation that keeps on growing and dividing. According to Lisa Coussens, a cancer biologist at the Comprehensive Cancer Center at the University of California, San Francisco, the abnormal growth may not be a tumor, but to the immune system, it looks like a wound that needs to be fixed. “When immune cells get called in, they bring growth factors and a whole slew of proteins that call other inflammatory cells,” she explains. “Those things come and go ‘heal, heal, heal.’ But instead of healing, you’re ‘feeding, feeding, feeding.’”2

Treating Chronic Inflammation

Of course, the intent behind all this research is to determine how to stop the inflammatory process that can cause disease in the first place. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen help inflammatory conditions, and many people take it to prevent heart attack and stroke. But NSAIDs can have significant side effects like gastrointestinal bleeding and liver damage.

The majority of the research on chronic inflammation has focused on fighting it with drugs, and there are many studies that have identified common drugs already in use that may help to reduce chronic inflammation. There also are some promising new drugs in development, as well as some studies that have identified proteins in the body that may help scientists to develop other new medications.

In February, researchers from King’s College London and clinicians from Guy’s and St. Thomas’ NHS Foundation Trust in London developed a protein agent modeled on the body’s own natural defenses to combat the inflammation that can destroy joints. The agent, binding immunoglobulin protein (BiP), is found in insufficient quantities in the joints of people with rheumatoid arthritis to have a therapeutic effect. Previous research indicates that giving a single intravenous dose of BiP quickly boosts a patient’s anti-inflammatory response by resetting their immune system. Now, the first human trial of BiP with up to 50 patients has started. “If BiP works as we expect,” says Gabriel Panayi, professor emeritus of rheumatology at King’s College London and honorary consultant rheumatologist at Guy’s and St. Thomas’, “then a single dose should be sufficient to put patients into remission for months.”¹²

Last year, scientists at Monash University’s Australian Regenerative Medicine Institute (ARMI) discovered an important step in the body’s process for healing wounds that may lead to a new way of treating inflammation. Building on previous research, they identified the enzyme, myeloperoxidase, that signals the leukocytes (that protect tissue from infection) to switch off once they are no longer needed for healing. “White blood cell activity is important for determining the balance between repair, scarring and healing. Understanding what regulates leukocyte activity during inflammation should ultimately allow us to manipulate this system and maximize healing and repair,” said lead researcher Professor Graham Lieschke of ARMI. “Our research has identified a new pathway to target with anti-inflammatory drugs. There is a significant need for new treatment options as current drugs are not effective in all circumstances.”¹³

Also this past year, researchers at University College London reported that, while studying the connection between inflammation and atherosclerosis, they found that the signaling protein in the blood called interleukin-6 receptor (IL6R) is responsible for an increased inflammatory response and that an existing anti-inflammatory drug is able to act on it. A companion study also found that a genetic variant in the IL6R gene reduces inflammation and subsequently lowers the risk of heart disease. Their results were similar to those found in trials of tocilizumab, an anti-inflammatory drug currently used to treat the inflammation of rheumatoid arthritis. The next step, according to the researchers, is to conduct clinical trials to prove that anti-inflammatory drugs prevent heart disease.¹⁴

In August 2012, the National Institutes of Health launched a multi-site trial to determine whether a common anti-inflammatory drug can reduce heart attacks, strokes and deaths due to cardiovascular disease in people at high risk for them. The Cardiovascular Inflammation Reduction Trial (CIRT) will determine whether treatment with methotrexate, a drug specifically targeting inflammation, reduces rates of cardiovascular events among adults who have had a heart attack within the past five years and who also have type 2 diabetes or metabolic syndrome. Methotrexate is an inexpensive generic drug commonly used at low doses to treat rheumatoid arthritis, and at higher doses to treat certain forms of cancers such as leukemias and lymphomas. Participants in the trial will be randomly assigned to receive methotrexate given at 10 mg to 20 mg weekly for three to four years or a placebo. In March, CIRT began to enroll 7,000 patients at 350 to 400 sites across the U.S. and Canada over the next two and a half years.¹⁵

Aside from medications, many physicians advocate adopting a more healthful lifestyle, which can have a profound impact on reducing chronic inflammation. Some foods and herbs have anti-inflammatory properties such as ginger, curcumin, rosemary, basil and cherries.9 While there is no evidence that an anti-inflammatory diet prevents inflammation, some believe that the Mediterranean-style diet does. Components of this diet include consuming whole-grain foods, unsaturated fats such as plant oils, fruits, vegetables, nuts, fish, poultry, eggs and moderate amounts of dairy foods, as well as avoiding red meat, butter, sweets and white foods such as rice, potatoes and pasta as much as possible.

The benefits of dairy and omega-3 fats are being proven. Researchers at the University of Tennessee’s Department of Nutrition conducted a study in which patients were given three-and-a-half servings of dairy daily over 12 weeks, which resulted in reductions in several markers of inflammation, as well as reduced blood pressure, compared with a group given just half a serving of dairy per day.5 The American Heart Association encourages people with heart disease to consume 1 gram of omega-3s a day from fish or supplements, which are believed to reduce inflammation.⁴ Researchers at Vanderbilt University are currently focusing on whether omega-3 fatty acids reduce the risk of colorectal cancers and diminish the production of inflammatory molecules.⁵

Then there is the uncharted area of nutrition: dietary supplements. Unlike prescription drugs, dietary supplements are not regulated by the U.S. Food and Drug Administration, and there are no requirements for them to undergo clinical trials for safety and effectiveness. However, some have shown to be effective. Cat’s claw (Uncaria tomentosa) has had modest benefits for easing rheumatoid arthritis joint pain and osteoarthritis knee pain during activity, according to limited studies. Devil’s claw (Harpagophytum procumbens) has been shown in studies to be effective in short-term treatment of osteoarthritic pain and is used extensively in Europe as an anti-inflammatory agent. Mangosteen (Garcinia mangostana) is credited with anti-allergy, antibacterial, antifungal, antihistamine and anti-inflammatory qualities and even as a possible cancer treatment. And, milk thistle (Silybum marianum) appears to protect the liver and block or remove harmful substances from the organ. It also appears to improve organ function in people with cirrhosis and in treating hepatitis.¹⁶ However, more study is needed to verify the effectiveness of all of these and other herbal supplements.

Exercise to promote weight maintenance is perhaps the newest advice for preventing inflammation. A significant discovery is how obesity promotes inflammation. Fat cells, particularly those in the visceral fat that settles in the belly and around organs, were long thought to store excess weight, but instead, they have been found to produce molecules known as cytokines that set inflammation in motion, says Dr. Libby. “We’ve learned that abdominal fat tissue is a hotbed of inflammation that pours out all kinds of inflammatory molecules,” he explains.⁵ In a study conducted at Tufts University, scientist Andrew Greenberg found that as fat cells reach their maximum size, they break down and die, and then macrophages, which are responsible for most of the inflammatory chemicals released in fat tissue, rush in to clean up the debris. “When fat cells die, macrophages surround the dead lipids the same way white cells surround a wooden splinter in your skin,” explains Greenberg. “The immune system is essentially surrounding and sequestering the dead fat cells and gorging on the leftover lipids and cellular debris,” which explains why obesity complicates arthritis, insulin resistance, diabetes and heart disease.⁹

Last, getting enough sleep, not smoking and keeping a positive attitude all are credited with reducing inflammation. Psychiatrists at King’s College London found that people who were physically or sexually abused as children are twice as likely to have significant levels of CRP, which explains why abused children show a higher incident of heart disease and diabetes as adults.⁹

Stay Tuned

Chronic inflammation is now recognized as a primary factor in the development of all kinds of chronic illness, including cardiovascular disease, obesity, autoimmune disorders, neurological disease and cancer. And researchers are working together in an effort to determine not only how this type of inflammation plays a role in these diseases, but also how to manage and prevent it. All that can be done now is to stay tuned as new discoveries become available to improve the health of millions of people across the world.