By Caroline Williams
Coping with modern life can sometimes feel like a remorseless treadmill. Many of us end up exhausted, with a vague feeling that all this pressure can’t be doing us any good. But we do it anyway, driven by the notion that stress is for wimps. And there’s always a glass of wine and a takeaway to look forward to at the end of the week. Big mistake. Far from being for wimps, physical and psychological stress are major triggers of a modern scourge that has been linked with every malady from heart disease, depression and chronic pain to neurodegenerative diseases.
That scourge is inflammation. Until recently, we have known little about how what starts as a protective immune process in the body goes awry, and there have been frustratingly few evidence-based suggestions on what we should do about it. But now we are starting to learn more about how the process works, how it connects body and mind, and what we might do to keep it in check. This new understanding is leading to treatments that may finally let us douse this constant fire — not by stopping it from happening, but by turning it off when it is no longer useful.
Such treatments could benefit the millions of people around the world who have chronic inflammatory conditions like rheumatoid arthritis, asthma and celiac disease. They could also assist those of us who want to have our cake, eat it and not end up inflamed. Finding a way to manage inflammation could help prevent modern life from damaging our long-term physical health.
“There’s no question, inflammation is everything,” says Charles Serhan, an immunologist at Harvard Medical School. “In the post-genomic era, understanding inflammation is the next frontier.”
Inflammation is the body’s first line of defense. Without it, we would be at the mercy of every pathogen going. When the body’s protective barrier has been breached by injury or infection, the classic inflammatory response brings redness, heat, swelling and pain. First, damaged cells secrete chemicals known as cytokines, which increase blood flow to the affected area and alert the rest of the immune system to prepare for a fight. Heat comes as a side effect of increased blood flow, redness as blood vessels dilate, bringing blood closer to the surface of the skin, and swelling happens as blood vessels become more permeable, allowing fluid and white blood cells to leak out and flood the tissue. These cells then attack and gobble up any invading pathogens, and later clear up the debris.
This basic response comes in different flavours, depending on what challenge the body is facing. If you sprain your ankle, for example, the joint swells and becomes hot, painful and difficult to move. If you have a cold, it is the blood vessels in the airways that swell, blocking the nose while inflammatory histamines stimulate mucus production, which in turn sets off coughs and sneezes. If you have flu, you get all of this, plus inflammation spreads throughout the body, causing joints and muscles to ache.
Throughout our evolutionary history, acute inflammation has mostly worked just fine, flaring up, tackling the problem and dying away again when the danger has passed. But now modern life is stacked against this delicate balance. Obesity, stress, pollution, bad diet and ageing can all tip us into a low-level state of inflammation that, rather than being confined to a specific tissue, keeps the entire body in a perpetual state of readiness for a threat that never comes.
This persistent background inflammation might not always make us feel ill, but it can store up problems for the future, from heart disease to type 2 diabetes and neurodegenerative disease. In 2008, immunobiologist Ruslan Medzhitov of Yale University dubbed this “para-inflammation” and argued that it is an unfortunate consequence of our longer, calorie-rich lives.
Stress is a particular problem. The hormone noradrenaline, which is released in anticipation of an impending life-or-death situation, sets off the same chain of events as an infection or injury. Yet although stresses passed quickly in our evolutionary past, these days many of us are walking around with a ticking time bomb of stress-induced inflammation that never quite goes away. “Chronic, low-grade inflammation is being discussed in our field as one of the main pathways linking stressful life conditions with disease,” says Nicolas Rohleder of Brandeis University in Massachusetts. Over the past few years, for example, Rohleder has found that the long-term strains of caring for a seriously ill family member, and a series of short-term stresses, both increase levels of inflammatory markers in otherwise healthy people.
Obesity is another inflammation-inducing modern disease. A small amount of body fat is healthy, and in fact necessary for regulating not just the immune system, but also appetite, mood and metabolism. Once the scales tip past 25 to 30 per cent body fat, however, the balance shifts. Body fat stores large quantities of inflammatory cytokines, and if there is too much fat on board, particularly around the organs, they can seep out, leading to ongoing, low-level inflammation. “Fat in large amounts is an inflammatory tissue,” says Derek Gilroy, an immunologist at University College London. “So you can envisage that lifestyle — eating the wrong food — throws these checks and balances out of kilter.”
Modern, high-sugar diets can also lead to gum disease. This can push the body into an inflammatory state that has been linked to an increased risk of atherosclerosis: fatty deposits in the arteries that are one of the main risk factors for heart attacks and strokes.
The longer these inflammatory markers hang around, the more likely they are to cause problems. These can be relatively minor, prolonging coldsby keeping up the response when it is no longer needed, for instance. Or they can be life-threatening. A recent study of nearly 300 people found that inflammation is directly linked to the early stages of heart disease. Over the course of three years, people with higher levels of reported stress and stress-related brain activity, not only had higher levels of C-reactive protein, a marker of inflammation, but also had a greater risk of cardiovascular disease. It seems that when there are higher levels of white blood cells in circulation, they get attracted to any fatty plaques accumulating in the arteries, making these more likely to build up and eventually rupture. This can lead the vessel wall to bleed and form a clot, which could go on to cause a heart attack or stroke.
Chronic inflammation might also increase the risk of depression. Many of the psychological symptoms that come with such inflammation — tiredness, malaise and a loss of appetite — look a lot like depression. Some people are beginning to wonder if a rumbling level of inflammation is behind at least some cases of depression and other mental health problems. This might be the reason why antidepressant drugs, which don’t reduce inflammation, are often ineffective.
The key then seems to be to keep the life-saving properties of the acute inflammatory response without allowing it to become chronic. But how?
One clue came in 2000 when Serhan and his team revealed that inflammation has an off switch. Until then, the reaction was thought to peter out as the immune cells that secrete cytokines gradually reduced in number and their effects became diluted. In fact, Serhan found that neutrophils and macrophages, the types of white blood cell that kick off the process, actively change tack once it has got going, releasing a second set of chemicals — called resolvins — that help mop up any remaining cytokines and sweep away any debris.
This made Serhan and others wonder whether chronic inflammation might be caused not by the on signals being turned up too high, but by a problem with the off switch. In the years since, he has been studying resolvins and related chemicals to see if there is a way to harness or mimic their actions.
One fly in the ointment is that there is so far no way to tell the difference between the various stages of acute inflammation — from a cut or cold, perhaps — and more troublesome chronic, low-level inflammation. That’s partly because immune cells and cytokines circulate around the body all the time, so any snapshot of the blood or tissues might make them seem inflamed when actually they are healthy.
Serhan thinks that looking at levels of circulating resolvins might be a better option. He has found that people with type 2 diabetes tend to have higher levels of cytokines in circulation, but lower levels of resolvins. This is relevant because the same white blood cells that kick-start the inflammation response should also step in to secrete resolvins to end it. So if someone has lots of cytokines but few resolvins, it is a sign of chronic inflammation — and a problem with the off switch. “I think that this can start to be diagnostic,” Serhan says.
He has also been working with periodontal researcher Thomas Van Dyke of the Forsyth Institute in Cambridge, Massachusetts, on a mouthwash containing resolvins. In rabbits, the mouthwash not only cleared up their inflamed gums, it also reduced inflammatory markers for cardiovascular disease. Human trials are now under way.
As well as finding ways to diagnose and treat low-level inflammation in healthy looking people, researchers are searching for drugs to stimulate the body to resolve inflammation in those with chronic conditions like arthritis and inflammatory bowel disease. The current generation of anti-inflammatory drugs, including steroids and non-steroidal anti-inflammatories such as ibuprofen and naproxen, inhibit the onset of inflammation, but do nothing to bring it to an end. Taking these drugs can reduce painful swelling in the joints, but by turning down the immune response, they leave people more vulnerable to recurring infections and less able to fight off a virus or recover from an injury.
“Chronic inflammation may be a main pathway linking stressful life with disease”
Increasing resolvin levels would help to solve the problem, rather than just mask its effects. Resolvins actively assist in ridding the body of bacteria and viruses, says Serhan, “so there is little to no chance for immune suppression or becoming vulnerable to recurring infections like there is with a lot of the current drugs”. It’s a win-win situation.
Although trials of new treatments are under way, the only drug currently available that has some resolvin-like effects is aspirin. It does block pro-inflammatory mediators, but Serhan’s group has found that low-dose aspirin has another unique ability: to trigger the production of more stable versions of natural resolvins. With currently available drugs, there is only one thing you can do to jump-start resolution of inflammation. “Take low-dose aspirin,” Serhan says.
That may soon change, however. Gilroy and his team are trialling a new drug called anabasum that mimics natural painkillers called cannabinoids in the body. So far, it is proving to work as well as a steroid at preventing inflammation but with fewer side effects. It also actively clears bacteria from wounds. “No matter how effective your drug is, if you don’t clear the antigen then inflammation won’t resolve,” says Gilroy. “It’s showing, at least in a healthy group of individuals, a pro-resolving effect that we simply don’t see and have never seen in any other drug.” The experiments he has done so far have been with skin inflammation, but the drug has since been tested in cystic fibrosis with promising effects.
Pain-relieving drugs could also benefit from a new understanding of how inflammation comes to an end. Resolvins have been found to regulate pain, and their receptors have been identified in the dorsal root ganglion, a kind of junction between the sensory nerves and the spinal cord. “If they can be harnessed therapeutically they could, in the future, replace opioids as a pain-control mechanism and one that would not lead to addiction,” says Serhan.
Gilroy, however, warns against getting too carried away with the resolvin story. The reason that inflammation seems to be the root of all health problems, he points out, is because it is not one thing, but many.
“The inflammation that we have in diseases like Alzheimer’s, cancer, autoimmune diseases like osteoarthritis, all of these are very different inflammatory processes,” he says. “It is hard for me to understand, given that there are many ways that a disease occurs, that they can resolve by the same mechanism.”
A Moving Target
This was demonstrated in recent experiments where Gilroy’s team injected bacteria under the skin of people with osteoarthritis — a painful condition characterised by chronic inflammation often due to autoimmune disease. Their osteoarthritis-related inflammation remained, but they had no problems in shutting down the skin-based inflammation that followed the injection. The two types of inflammation, and their resolution pathways, seemed to be completely different. This is also true for the same disease in different people, as well as for different tissues in the same person, says Gilroy. Then there are gender differences in susceptibility: for some unexplained reason, women are far more likely than men to get autoimmune diseases. “Inflammation is not inflammation,” says Gilroy. “The requirements to resolve that process will be, I think, disease, organ and circumstance specific.”
Pinning down the solutions — and even figuring out which to use in which instance — won’t be simple. “It’s like you walk into a bar and there is a great big bar-room brawl, but you don’t know who is involved, and you don’t know who started it and how it’s going to end up,” says Gilroy. “Teasing and separating these separate factions will make it much easier to understand the processes going on.”
While we wait for these insights, there are simple things we can do at home to keep inflammation at bay. All of the resolvins so far identified are made in the body from omega-3 essential fatty acids. These aren’t produced in the body to any great extent, so can only come from the diet, the richest source being oily fish. Making sure we get the recommended three weekly portions of oily fish, or equivalent, might help ensure that our bodies have enough raw material to wind down inflammation, says Serhan. The link between omega-3s and the resolution of inflammation might explain why a diet rich in these is associated with a lowered risk of heart disease.
Studies also link diets containing more fat and sugar to inflammation. This, combined with research suggesting that pigments found in fresh fruit and vegetables help to regulate inflammation, indicate that the standard advice about eating well applies here too: consume fewer processed foods and plenty of whole grains, fruit and vegetables.
Certain kinds of exercise seem to help, too. In recent experiments in rats with inflammation of the back, stretching the affected muscles twice a day stimulated the release of resolvins within the muscle, which enabled the rats full to regain movement and heal more quickly than control rats. The team that did this work, led by Lisbeth Berrueta of Harvard Medical School, is investigating whether this “yoga experiment” works in human volunteers.
Exercise in general certainly seems to tackle inflammation. Admittedly, it causes a spike of the cytokine IL-6 in the muscles and blood, which is often taken as a sign that inflammation is on its way. Yet according to Mark Febbraio of the Garvan Institute in Sydney, Australia, who discovered the effect in 2008, in this case, IL-6 works as an anti-inflammatory molecule, peaking only briefly before signalling to the liver to metabolise fat and remove excess IL-6 from the blood. So, Febbraio says, unless it leads to injury, there is no amount of physical activity that will push you into an inflammatory state. “Exercise is completely anti-inflammatory. Even in heavily trained athletes, most of the time IL-6 is [very low],” he says.
But you don’t need to be training for triathlons for exercise to help tamp down inflammation. Researchers have found that even a 20-minute stroll can be enough to make a difference.
Beyond advice to eat well and exercise, these days it seems everyone from celebrity chefs to pop stars has a quick-fix tip for how best to fight inflammation. So is there a sliver of substance to endorsements of basil-leaf infused bubble baths or turmeric lattes? The jury is out. Curcumin, the active ingredient in turmeric, has anti-inflammatory properties in cells in a Petri dish, but clinical trials in humans have so far been underwhelming. This might be because most of it passes through the body without being absorbed. Likewise, quite how the basil in your bath is supposed to infuse into your body is anyone’s guess. On the other hand, if it helps you unwind — and as long as following the latest fads doesn’t become a source of stress on its own — go for it. In the fight against chronic inflammation, every firefighter helps.