Inflammation overload: It could be a sign of trouble
■ The evidence is strong for a link between atherosclerosis and inflammation, and it is building for diabetes, with new studies in search of treatment options.
Inflammation in the body is a good, protective and healing mechanism -- except when it isn't. In other words, the white blood cells that hurry to the site of infection and injury actually might be possible harbingers of trouble ahead.
Investigators are examining the cascading series of events initiated by long-term inflammation that, they suspect, may culminate in such serious chronic illnesses as heart disease, diabetes and Alzheimer's.
But ascertaining the practical results of this insight is still a matter of inquiry. For instance, new clinical trials are being launched to explore inflammation's role in heart disease and whether a commonly used anti-inflammatory medication can reduce blood glucose levels in people with type 2 diabetes. Researchers already have determined that obesity is associated with a state of chronic low-level inflammation.
"Over the past five to eight years, it's becoming increasingly clear that a lot of these chronic diseases that were thought to be unique have similarities in that they are mediated by inflammatory processes that persist over many years," said Achsah Keegan, PhD, professor of microbiology and immunology at the University of Maryland and a researcher at the school's Center for Vascular and Inflammatory Diseases in Baltimore.
The common wisdom eventually could be summed up with this statement: Unhealthy lifestyles can trigger chronic inflammation, and a body on fire provides a scary visual. Thus, understanding this dark side may help answer many "why" and "how" questions in the exam room -- such as "Why should I walk more and lose weight?" and "How do diet and exercise lower the risk for heart disease, diabetes, and perhaps cancer and Alzheimer's?"
As researchers set out to connect the dots between inflammation and disease, they do not expect their findings to change the basic advice given to patients. "All the things we're supposed to be doing, like eating right and exercising, all play a role in reducing inflammation," said Mark B. Taubman, MD, director of the Cardiovascular Research Institute at the University of Rochester Medical Center in New York.
So far, the evidence is most solid for a link between inflammation and atherosclerosis. "I would say that it is absolutely accepted that a major part of atherosclerosis is inflammation of the inner arterial wall," said Dr. Taubman, who is embarking on a study funded by the National Heart, Lung and Blood Institute to try to understand how such inflammatory processes increase heart attack risk.
Although the concept that there could be an inflammatory component to atherosclerosis was considered for decades, it wasn't fully appreciated until relatively recently, said Neal Weintraub, MD, director of the University of Cincinnati Medical Center's Division of Cardiovascular Diseases.
Most cardiologists now believe that the reaction of the body's immune system to fatty buildup in the arteries creates the heart attack risk. Vessel walls mistake fatty deposits for intruders similar to bacteria and call on the white blood cells for help. Those cells invade the arterial wall, eat cholesterol and start to develop a plaque that narrows the vessel, Dr. Taubman said.
He and his colleagues are trying to understand the molecular basis for two changes that promote this scenario -- what summons the white cells to the arteries in the first place and what makes them stick to the endothelium.
Reactive oxygen species, high cholesterol, high blood pressure and high blood glucose all can transform the endothelium into a magnet for the cells, Dr. Taubman said. "By modifying the risk factors, you are essentially decreasing the signals to the endothelial cells that tell them to switch from being good to being bad."
Several related projects are under way at the university, all attempting to answer the question of whether these intracellular signaling pathways can be manipulated to reduce inflammation in blood vessels. The projects have the potential to produce new treatments.
But the steps to achieve this aren't clear. For instance, even common infections such as the flu have been considered players in the onset of atherosclerosis, although the evidence is not strong, Dr. Taubman said. "Every 10 years somebody has a theory. It was Chlamydia for a while."
Plus, there may be many causes of inflammation that exacerbate atherosclerosis, Dr. Weintraub said. Some infections appear to be linked more strongly to this mechanism than others.
Periodontal disease is one possible cause that is attracting attention, and there also are probably subsets of patients with different levels of vulnerability to inflammation, he said. "We don't understand that yet, so we tell all our patients to lose weight, exercise and eat right."
He also would strongly recommend a flu shot as a very safe, economical and important treatment.
Statins apparently also are effective at lowering inflammation along with high levels of bad cholesterol, said Richard M. Ransohoff, MD, director of the Neuroinflammation Research Center at the Cleveland Clinic.
"When statins were introduced for the treatment of high cholesterol, the benefits became apparent much more quickly than anyone would have predicted. That led researchers to discover their anti-inflammatory properties."
Diabetes risk scrutinized
Another anti-inflammatory medication, salsalate, is about to be put to the test to lower the risk of type 2 diabetes, which is now reaching epidemic levels throughout the world.
Principal investigator Steven E. Shoelson, MD, PhD, associate director of research at the Joslin Diabetes Center in Boston, along with colleagues at several sites around the country, are recruiting 800 adults with poorly controlled type 2 diabetes for a multicenter clinical trial -- Targeting Inflammation using Salsalate in Type 2 Diabetes or TINSAL-T2D. Salsalate is used primarily to treat arthritis pain.
Findings from earlier trials point to a similar mechanism at work for cardiovascular disease and diabetes, he said. "Obesity-induced inflammation is upstream of both."
The role of inflammation generally has been embraced by the cardiovascular treatment community because it is backed by more abundant trial data. Although the diabetes treatment community is coming to that same conclusion, it is still less widely accepted, he said. "I would call it a hypothesis that is being born out again and again. It is being proven, but I wouldn't say it is fully accepted."
TINSAL-T2D "is the first large-scale study in patients that tests whether reducing inflammation can actually be used to treat diabetes," Dr. Shoelson said. "Given what we are learning about how type 2 diabetes develops, we think this might be getting at an underlying cause."
"We're looking right at the heart of the problem and saying, 'Let's give it a gung ho with an anti-inflammatory and see what that does.' " Researchers have conducted three small trials in people with diabetes and one trial for prediabetics, and all were positive.
"The outcome of this study has the potential for significant public health benefit," said Myrlene Staten, MD, senior adviser for diabetes translational research at the National Institute of Diabetes and Digestive and Kidney Disease, which is funding the study. "If salsalate improves the control of type 2 diabetes, we would have an inexpensive addition to our arsenal of drug options," she noted in a statement.
The researchers also will be testing salsalate's ability to lower the risk for coronary heart disease in a separate study scheduled to start soon at one trial site.
Atherosclerosis and diabetes are among the chronic conditions backed by the strongest evidence that an inflammatory component is in play. But asthma, cancer and Alzheimer's also are thought by some to follow this route.
The role inflammation plays in Alzheimer's disease, however, remains a mystery. One large clinical trial testing the benefits of two nonsteroidal anti-inflammatory drugs was halted in December 2004 when the drugs were found, in other trials, to increase heart attack risk.
In Alzheimer's, an accumulation of amyloid plaques is thought to trigger a harmful response. "Like anything else that accumulates where it's not supposed to, it initiates an inflammatory response," Dr. Keegan said.
Plus, a connection exists between vascular risk and dementia, said Margaret Gatz, PhD, professor of psychology, gerontology and preventive medicine at the University of Southern California in Los Angeles. "What has gotten more clear is that those connections are also important for Alzheimer's disease," she said. "So people are looking at things like diabetes and midlife hypertension as risk factors for Alzheimer's disease." And inflammation is also in this picture. "The inflammatory hypothesis has a lot of merit as a way of pulling together some findings."
Researchers from various specialties also are creating centers to focus more on this hypothesis. The University of Maryland gathered scientists from diverse backgrounds for its hub in Baltimore, said Dr. Keegan, who is an immunologist there. The idea was to break down barriers. "If someone had been working in vascular diseases or cardiology, they wouldn't be paying much attention to immunology, and vice versa."
The center at the Cleveland Clinic is another recent arrival. "It's a new concept, an indication that inflammation is piquing interest," Dr. Ransohoff said. "I think it's an area of research that is not that far from being clinically applicable."