September 4, 2004

INFLAMMATION is known as the response to cell injury that involves dilatation of small blood vessels, redness, warmth, pain, and migration of white blood cells to the region as part of the healing process that removes toxic substances and damaged tissue. In short it is a response of body tissues to injury or irritation; characterized by pain, swelling, redness and heat.

Now that we know that inflammation is the body’s first line of defense against cuts, scrapes and infections, we also need to consider the fact that this familiar healing response has been implicated in a whole swarm of different diseases.

Inflammation is known to play a role in diseases that involve an overactive immune system, such as asthma, allergies and autoimmune conditions like rheumatoid arthritis. But barely a month goes by now without researchers announcing fresh evidence implicating the cells and chemicals of the inflammatory response in some new disease.

So what is going on? Have we misunderstood the role of inflammation in the body all this time? Is there some factor that links all these diseases together?

The mystery has not yet been solved, but as a growing number of researchers in different specialties are focusing their efforts on the same area, important insights are emerging. The explanation may be simply that while the conditions have different causes, and involve diverse organs and tissues, the inflammatory response helps continue the disease process. So inflammation is not the cause of all these diseases, it turns out, but it may help some of them persist.

The new take on inflammation is all surprising because the mechanisms behind this biological process have been known for decades. After a scrape or knock, or an invasion by viruses or bacteria, nearby cells send out chemical signals, or cytokines, that increase blood flow to the area and recruit immune cells complete with their formidable array of chemical weapons. In contrast to the second-line adaptive immune response, which involves antibodies and immune cells directed against specific foreign proteins, this first-line reaction is immediate and indiscriminate.

That means the inflammatory cells can harm innocent bystanders. “They can inflict friendly-fire damage on tissues,” says John Savill of the University of Edinburgh’s Centre for Inflammation Research. If the inflammation is short-lived, such damage is usually negligible. But sometimes the inflammation doesn’t die away quickly, and that’s when the serious problems start. “A long-forgotten injury gives rise to a persistent inflammation response that’s now dangerous,” he says. “It becomes a cause in itself of disease.”

Perhaps the best example is the role of chronic inflammation in heart disease. The conventional view was that this common condition was similar to a plumbing problem. High blood cholesterol levels caused fatty plaques to build up inside artery walls, limiting the blood supply to the heart. And if the plaque disintegrated and caused a blockage in narrower vessels downstream, this could trigger a heart attack. The new thinking, however, is that while these processes play their part, inflammation of the artery walls is another factor, which causes the plaque both to build up and to disintegrate.

The part inflammation plays in other conditions may be less clear-cut, but the circumstantial evidence for an important role is certainly compelling. Since the early 1990s doctors have been intrigued by the fact that arthritis patients who take anti-inflammatory painkillers known as NSAIDs for many years are less prone to Alzheimer’s. Inflammatory cells have also been found in the brains of people with this form of dementia. NSAIDs work by inhibiting COX-2, a key intracellular enzyme involved in inflammation and pain. COX-2 has been found to occur at higher levels in most human breast cancers, but the enzyme has many effects and it is unclear which is most important in promoting tumor growth.

So what could be causing the inflammation to persist in all these diverse diseases? Until recently, most scientists put long-term inflammation down to some sort of lingering alarm signal that kept calling out the troops. A persistent infection could be responsible, say, or, in the case of autoimmune diseases, mistaken recognition of one of the body’s own proteins as foreign. Immunologists assumed that without the alarm call, the inflammation would just fizzle out. That assumption turns out to be wrong.

The first signs that something more interesting was going on came about a decade ago. A team headed by Charles Serhan, a biochemist at Harvard Medical School, was studying the chemical signals involved in triggering inflammation in mice when they found something that did not fit. One class of molecules they came across, called lipoxin, recruits ancestors of immune cells called macrophages, which gulp down bacteria, dying cells and debris. But instead of bringing in the macrophages primed and ready for battle, the lipoxin calmed them down and stopped them from continuing the inflammatory response.

Serhan’s group began studying this curious behavior more carefully. In time they discovered a complex network of signaling molecules whose role is to damp down, or settle, inflammation. One class of these signals, which Serhan named “resolvins”, turned out to be derivatives of omega-3 fatty acids, which may help explain why a diet rich in these fats cuts the risk of heart disease. “That was completely unexpected,” says Serhan.

Now that Serhan had shown that resolving inflammation was an active process, not just a default pathway, it made more sense to ask why resolution sometimes fails. After all, in most people, inflammation normally dies down in a few days. If it didn’t, every thorn-prick would be a disaster. “That has been the million dollar question in inflammatory disease,” says Serhan. “It isn’t obvious why some inflammations resolve and others persist.”

“An important factor”, Serhan says, “could be the kind of funeral given to the immune cells called neutrophils that flood in during inflammation. If all goes well, these cells die within two or three days in a carefully controlled process known as apoptosis, and are eaten by macrophages before their contents escape. Neutrophils undergoing apoptosis display a special chemical on their cell surface called phosphatidylserine (PS), which triggers the macrophages to release cytokines such as transforming growth factor beta (TGF-beta) that actively promote resolution.”

But sometimes neutrophils get a different sort of send-off. If for some reason the apoptosis program fails, they die a messier death, known as necrosis. Lacking the PS signal, macrophages fail to eat them in time, and their contents, including pro-inflammatory cytokines, leak away.

So what signs are there that these processes play a role in human diseases involving persistent inflammation? Perhaps the best evidence is in the autoimmune disease rheumatoid arthritis, which has a major inflammatory component. Problems with the resolution of inflammation also appear to play a role in other autoimmune diseases. In healthy people, apoptotic cells are normally cleared away so fast you never find them lying around. But two years ago Martin Herrmann, an immunologist in Germany, found them in several tissues. “Wherever you look, you see more apoptotic cells lying around than normal,” he says.

Crucially, it is not only the conventional inflammatory diseases where these molecular pathways seem to play a role. In heart disease, the plaques that line artery walls are full of the debris of apoptotic cells. And a team led by Martin Bennett, a cardiologist showed a few years ago that hunting cells such as macrophages in plaques recognize the PS signal that triggers apoptosis. So why doesn’t the apoptosis process help the inflammation resolve? “It is now known that the oxidized lipids present in the plaque can bind to PS receptors on hunting cells, which, theoretically at least, could prevent clearance of the apoptotic cells”, says Bennett.

The relevance of this work to other diseases is still unknown. But this growing understanding of the importance of resolution offers scientists a second front in the fight against diseases that involve chronic inflammation - whether or not failure of resolution is where the primary defect lies. And if existing anti-inflammatory drugs are anything to go by, they could prove incredibly versatile. Current anti-inflammatories target the other end of the process - the signals that trigger inflammation.

Drugs that prevent inflammation from the starting can interfere with defense and can leave patients vulnerable to infections. Drugs aimed at enhancing the resolution phase, on the other hand, would in the main preserve the immune system’s rapid response to injury or invasion, while ensuring that inflammation gets turned off once that task is accomplished. “They shouldn’t affect the onset phase, which is a good thing,” says Bennett. “It may be a clearer way of allowing the immune system to do its job and then switching it off when it has to.”

A few hints of success have emerged as far as these drugs are concerned. Serhan’s group found two years ago that when mice with asthma were exposed to allergy triggers, the cells lining their airways pumped out more lipoxin, LXA4, to damp down the inflammation. Giving artificial LXA4 boosted this natural resolving mechanism, reducing inflammation and opening the airways of the mice. Mice genetically engineered to carry the human receptor for LXA4 showed a similar improvement, suggesting that the therapy could work in people as well.

Helping macrophages clear away apoptotic cells from the site of inflammation could also improve resolution. Scientists are now doing test-tube studies to see whether two signaling molecules, GCSF and GMCSF, will make macrophages more willing to eat up apoptotic cells and favor resolution. Bennett, too, is looking at drugs to enhance apoptotic clearance, but he says the work is at too early a stage to discuss as yet.

Of course, pro-resolution drugs could have side effects. For example, the pro-resolution TGF-beta produced by macrophages can promote scarring - an appropriate response after tissue injury. But scarring is a serious problem - sometimes the most serious - in inflammatory diseases of the nervous system and lungs.

A second downside is that they could theoretically leave people more vulnerable to parasites. Many parasites dodge the immune system in part by sending out their own resolution signals. For example malaria parasites prompt infected red blood cells to display on their surface the PS signal normally used by inflammatory cells undergoing apoptosis. This, again, may calm the immune system and may help explain why anti-malarial vaccines have been so hard to develop, says Herrmann.

After knowing all that one can only come up to this conclusion that immunologists have a lot more work to do in figuring out how the various resolution signals fit together to halt inflammation. And it will be years before they know for sure whether enhancing these signals will produce safe and effective medicines. But the evidence is certainly pointing that way. The rest we’ll have to wait and watch.

The writer contributes regularly to Sci-tech World on science-related issues

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