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Friendly FireMichael Glenwood

Friendly Fire (continued)

THERE’S A NEW BUZZ among scientists about inflammation, even though it’s been known for ages to be one of the first responses by the immune system to infection and irritation. Inflammation is hot. And not in just a classical “calor” kind of way. Calor—as in heat or fever—is one of four characteristics of inflammation recorded in De medicina, an ancient Roman medical text. The remaining three—dolor, rubor and tumor—translate to pain, redness and swelling, respectively.

“Inflammation is something we have rediscovered in the 21st century,” explains Shyam Biswal, PhD, MS, a professor in Environmental Health Sciences (EHS), “specifically, inflammation as a focal point of chronic disease. People used to think of it as a bystander of disease. But it’s actually a driver.”

If attention to inflammation is spreading like wildfire throughout the research world, an early spark was ignited by Noel Rose, MD, PhD, director of the Center for Autoimmune Disease Research. Having introduced the concept of autoimmunity as a cause of chronic thyroiditis in 1956, Rose now is investigating the causes of magnified inflammatory responses in the hearts of young men for whom transplant is the only cure. A muscle that needs to pump, Rose concedes, is a bad location for excessive scarring to occur as a result of inflammation.

“We’re now looking at the details of inflammation,” he says, “and realizing the benefits from targeting specific parts of the inflammatory response. You have to know which part is doing good and which is doing bad and tailor drugs accordingly.”

It’s not simply the presence or amount of inflammation that’s important, Rose says: “It’s the texture of it; the makeup of the cells that are attracted, the ways in which they are stimulated and the products they release. If you’re getting down to that level, that’s where you find the causes of diseases.”

Among chronic, noninfectious disorders now commonly regarded as “inflammatory” is atherosclerosis, often called hardening of the arteries, says Josef Coresh, MD, PhD ’92, MHS ’92, director of the George W. Comstock Center for Public Health Research and Prevention.

“We’ve known for a long time that inflammation is central to atherosclerosis,” says Coresh, principal investigator of the Johns Hopkins Field Center of the Atherosclerosis Risk in Communities (ARIC) study. “You can see inflammatory cells in the lesions.” (Known as plaques, lesions form in the arteries, hardening them.)

The prospective ARIC study, which first examined 15,792 Americans in 1987 and has followed them ever since, is a key resource for the investigation of many inflammation-related chronic diseases—few of which show their hands so obviously as atherosclerosis.

Researchers who are sleuthing the origins of cancers and diabetes, for instance, have found themselves stumbling time and again on inflammatory roots. Apparently, long ago resolved and seemingly unrelated infections buried deep in people’s pasts might tip the precarious immune system balance, imperceptibly if irrevocably reprogramming it. So too might the persistently simmering, subclinical kind of inflammation caused by excess body fat, for example. One investigative focus is finding the mechanisms that link long ago infections to inflammation and later, chronic diseases. Another is dissecting and tinkering with processes that can block, enhance or otherwise regulate inflammation once the SWAT team has mutinied.

For instance, Andy Pekosz, PhD, with collaborators from Johns Hopkins Medicine, has demonstrated that epithelial cells harvested from the noses of patients suffering from chronic sinusitis “remember” many generations later that they are different. These cells have comparatively heightened inflammatory responses to various stimuli a month after leaving a diseased nasal environment—despite having been grown and propagated under the same conditions as healthy cells in lab culture dishes.

“This tells us there’s something about these cells that has changed,” explains Pekosz, an associate professor in the W. Harry Feinstone Department of Molecular Microbiology and Immunology (MMI). “The detection machinery or the circuitry in the cells from sinusitis patients is reprogrammed to respond differently to factors that stimulate inflammation.”

Understanding this reprogramming of the inflammatory response itself is the holy grail for Pekosz.

“If we could understand how to tune down that heightened response by the epithelial cells, we could relieve the chronic sinusitis,” he says. “The flip side is, if we could, at an opportune and early time point, find a way to increase the inflammatory responses, we might have a very powerful broad tool to use against a number of different viruses, for instance.”

Fiddling even a bit with any discrete part of a delicate and complex system is not without unforeseen consequences, many of which could be perilous, if not immediately, then sometime in the future. (Case in point: Although it provided sweet relief for many with osteoarthritis pain, the anti-inflammatory drug Vioxx, which works by inhibiting an enzyme in the inflammatory pathway called COX-2, was withdrawn from the market in 2004 after a study showed it doubled patients’ risk of heart attacks and strokes after 18 months of use.)

The inflammatory system is like the ocean, according to Coresh: “It’s beautiful, but also deadly,” he says. “As long as it’s calm, you can conduct commerce and fish on it, and without it, you’re dead. But, if it storms, it’s incredibly powerful and can kill you.

“When there’s imbalance in one thing, it’s like a wave that pushes on other things and you get a whole cluster of effects.”

“It’s not simply the presence or amount of inflammation that’s important. It’s the texture of it. That’s where you find the causes of diseases.”
— Noel Rose


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