What does a splinter in your finger or an ingrown toenail have to do with your risk of developing Alzheimer's disease, a heart attack or bowel cancer? More than you might think. As scientists delve deeper into the root causes of these and other diseases, they are seeing more and more links to an ancient immunological defence mechanism called inflammation - the same biological process that reddens the tissue around a splinter and causes swelling with pus around the ingrown nail. If they are right, and it looks like they are, this could radically change the prevailing theory of what makes us sick.
Most of the time, inflammation is a lifesaver that allows our body to fight off various disease-causing bacteria, viruses and parasites. As soon as one of these potentially deadly microbes enters the body, our immune system triggers an inflammatory response that eliminates both the invader and the potentially infected tissue. The process then subsides just as quickly and healing begins.
Occasionally, however, the inflammatory reaction does not disappear immediately. Sometimes the problem is a genetic predisposition, in other cases smoking or high blood pressure, for example, perpetuates the process. In this case, the inflammation becomes chronic rather than transient, with after-effects that appear to underlie a variety of diseases. The chronic inflammatory processes do not always have to be immediately associated with symptoms and can lie dormant in the body for years as „silent inflammation“. Sometimes they can be detected during routine blood tests using various parameters, such as the highly sensitive CRP, which is mentioned below.
In recent years, silent inflammation has become one of the hottest topics in medical research. Hardly a week goes by without another study being published that reveals a new way in which chronic inflammation can damage the body. It destabilises cholesterol deposits in the coronary arteries and leads to heart attacks and possibly even strokes. It attacks nerve cells in the brains of Alzheimer's patients. It can even promote the growth of abnormal cells and their transformation into cancer cells. In other words, chronic inflammation can be the driving force behind many of the most feared diseases of middle and old age.
This concept is so intriguing because it suggests a new and potentially much simpler way to defend against disease. Instead of different treatments for heart disease, Alzheimer's and bowel cancer, for example, there could be a few anti-inflammatory agents that prevent all three diseases.
Chronic inflammation also fascinates scientists because it suggests that, from an evolutionary perspective, our bodies may have become victims of their own success. We have evolved as a species because we can fight off microbial invaders. The strategies our bodies used to survive were important in a time when we had no treatment plants to purify our water and no sewers to protect us from infection.
But now that we are living longer, these same inflammatory strategies are more likely to spiral out of control. To make matters worse, many of the characteristics of a Western lifestyle - such as a diet high in sugar, meat and saturated fats, accompanied by little or no exercise - also make it easier for the body to maintain inflammatory processes.
To better understand what immune defence is all about, it's helpful to know a little about the basic immunological response that is triggered when the body is exposed to trauma or injury. Once that splinter is lodged in your thumb, for example, specialised sentinel cells travelling throughout the body alert the immune system to the presence of foreign bodies and bacteria that may have entered with the splinter. Some of these cells, called mast cells, release a substance called histamine, which causes nearby capillaries to leak. This allows small amounts of plasma to leak out, slowing the spread of invading bacteria and allowing other more distant immune defence cells to easily reach the site. Meanwhile, another group of cells, called macrophages, begin an immediate counterattack, releasing more messenger substances called cytokines that promote the inflammatory response. Soon, masses of immune cells flood the centre of inflammation, destroying pathogens and damaged tissue alike.
Doctors call this general reaction to practically any kind of external invader „innate immunity“. Even the bodies of animals as primitive as starfish defend themselves in this way. However, higher organisms have developed a more precise defence system that supports and reinforces the innate response by producing so-called antibodies that are specifically tailored to certain types of bacteria or viruses. This „learnt immunity“ makes it possible, for example, to develop vaccines against diseases such as smallpox and influenza. The innate and learned immunological defences work together until all invading germs have been destroyed. In a final burst of activity, a last wave of cytokines is released, the inflammatory process recedes and repair and healing begins.
Problems begin when, for one reason or another, the inflammatory process persists and becomes chronic, the effects vary and depend greatly on where in the body the out-of-control response starts. Among the first to recognise the wider effects were heart specialists, who noted that inflammation appears to play a key role in cardiovascular disease.
Not so long ago, most doctors thought of heart attacks as an isolated disease process. Over the years, fatty deposits slowly built up on the insides of the coronary arteries until they became so large that they cut off the blood supply to a vital part of the heart. A complex molecule called LDL, or bad cholesterol, provided the raw material for these deposits. Obviously, anyone with high LDL levels had a higher risk of developing heart disease.
However, this is not true in every case: half of all heart attacks occur in people with normal cholesterol levels. Not only that, as imaging techniques improved, doctors were surprised to discover that the most dangerous plaques were not that big. Something that had not yet been identified was causing these deposits to burst, triggering massive clots that disrupted the coronary blood supply. In the 1990s, scientists were convinced that some kind of inflammatory reaction was responsible for the bursting of the plaques and set out to prove this.
To support this assumption, a simple blood test was developed that served as a marker for chronic inflammation, the C-reactive protein (CRP), a molecule produced by the liver in response to an inflammatory signal. During an acute illness, such as a severe bacterial infection, CRP levels rise rapidly from less than 10 mg/L to 1,000 mg/L or more. However, the researchers were more interested in the low CRP levels, less than 10 mg/L, that they found in otherwise healthy people, which indicated only a slightly elevated level of inflammation. In fact, the difference between normal and elevated is so small that it needs to be measured using a specially developed procedure called a high-sensitivity CRP test.
It was shown that healthy middle-aged men with the highest CRP levels were three times more likely to suffer a heart attack in the next six years than men with the lowest CRP levels. Finally, the inflammation experts found that a CRP level of 3.0 mg/L or higher can triple your risk of heart disease. The risk appears to be even greater in women than in men. In contrast, people with extremely low CRP levels of less than 0.5 mg/L rarely have heart attacks.
Doctors still don't know exactly how inflammation can cause a plaque to burst. But they do have a theory. When the LDL cholesterol level in the blood rises, they suspect, some of it becomes lodged in the lining of the coronary arteries. Macrophages, which react to foreign bodies, join in and try to remove the cholesterol. If for some reason the cytokines that are released start to drive the inflammatory process instead of containing it, the plaque becomes unstable. This is not about downplaying high cholesterol as a risk factor. Cholesterol deposits, high blood pressure and smoking all contribute to the development of underlying plaques. What inflammation seems to do is make these plaques more prone to rupture and cause a heart attack. If there is only inflammation, but no underlying heart disease, then there is no problem.
Cardiologists do not currently recommend testing the general population for inflammation levels. However, there is a growing consensus that CRP should be measured in people with a moderately increased risk of developing cardiovascular disease.
Before Dr Frederick Banting and his colleagues at the University of Toronto isolated insulin in the 1920s, doctors tried to treat diabetes with high doses of salicylates, a group of compounds similar to Aspirin®. Although the administration of salicylates reduced sugar levels, it came at a high price: side effects included constant ringing in the ears, headaches and dizziness. Today's diabetes therapy is much safer and works by either replacing insulin, increasing the body's own production or helping to utilise the hormone more efficiently. In recent years, researchers have re-examined the salicylate approach for evidence in the treatment of diabetes.
What they have discovered is a complex interplay between inflammation, insulin and fat - either that in the diet or in the body's adipose tissue. In fact, fat cells behave very much like immune cells and produce pro-inflammatory cytokines, especially when you gain weight. How inflammation fits into this scenario - either as a cause or an effect - remains unclear at present. However, the case for a central role of inflammation is growing stronger. Researchers have bred a strain of mice whose fat cells are veritable inflammation factories. The mice process insulin less efficiently and subsequently develop diabetes.
This suggests that blocking the inflammatory process in time could reverse some of the effects of diabetes. Some of the drugs already used to treat the disorder, such as metformin, may work as they also dampen the inflammatory response. In addition, preliminary research suggests that high CRP levels may indicate a higher risk of diabetes. However, it is still too early to say whether reducing CRP levels actually keeps diabetes at bay.
As early as the 1860s, the pathologist Rudolf Virchow suspected that cancerous tumours could develop at the site of chronic inflammation. A century later, oncologists investigated the role that various genetic mutations play in the development of cancer cells. Now researchers are investigating the possibility that mutation and inflammation are mutually reinforcing processes that, if left unchecked, can turn normal cells into potentially lethal tumours.
Sometimes the reason for the initial inflammatory process is obvious - as in the case of chronic heartburn, where the oesophageal mucosa is constantly in contact with stomach acid, which is a risk factor for oesophageal cancer. In other cases, it is less clear. Scientists are investigating the role of an enzyme called cyclooxygenase 2 (COX2) in the development of colorectal cancer. COX2 is another protein that the body produces during inflammation.
In recent years, researchers have shown that people who take acetylsalicylic acid daily - which is known to block COX2 - are less likely to develop precancerous lesions called polyps. The problem with acetylsalicylic acid, however, is that it can also cause internal bleeding. The group of COX2 inhibitors mentioned above does this to a much lesser extent.
When doctors treating Alzheimer's patients looked more closely at who got the disease, they discovered an interesting correlation: those who were already taking anti-inflammatory drugs for arthritis or heart disease tended to develop the disorder later than those who were not taking these drugs. Perhaps the immune system mistook the characteristic plaques and debris that accumulate in the brains of Alzheimer's patients as damaged tissue that needed to be removed. If so, the resulting inflammatory response was more harmful than beneficial. Blocking it with anti-inflammatory agents could limit or at least delay the damage to cognitive function.
The most likely culprits this time are the glial cells, whose job it is to nourish the neurones and communicate with them. Researchers have discovered that glial cells can also have an immunological effect similar to mast cells and produce inflammatory cytokines that trigger further immune reactions. The glial cells try to restore the brain to a normal state. But for some reason, the process seems to be out of control in neurodegenerative diseases such as Alzheimer's disease. Here, chronic glial activation is seen, leading to an inflammatory state.
It seems that some people are more sensitive to plaques and deposits than others. Perhaps they have a genetic predisposition. Or perhaps a prolonged bacterial infection such as gum disease maintains the internal centres of inflammation and unbalances the body towards chronic inflammation.
Preliminary research suggests that low-dose acetylsalicylic acid and omega-3 fats, which are known to reduce inflammatory cytokines, appear to reduce a person's risk of Alzheimer's disease. Unfortunately, most of these preventative measures need to be initiated early before neurological problems develop. It has been shown in dementia that it is very difficult to improve symptoms that are already there. But it may be possible to stabilise patients and prevent further deterioration.
No one has more experience in treating chronic inflammation than the doctors who specialise in rheumatoid arthritis, multiple sclerosis, lupus and other autoimmune diseases. These diseases are the clearest example of an organism at war with itself. What drives its internal destruction, however, does not come from excess cholesterol deposits or a stubborn bacterial infection. Instead, the body's highly developed, learned immunological defences mistakenly attack healthy cells in the joints, nerves or connective tissue with an inflammatory attack.
In recent years, powerful drugs aimed at inhibiting certain inflammatory cytokines have worked wonders against rheumatoid arthritis and other autoimmune diseases. But as is so often the case in medicine, these drugs also cause some problems. Some patients are slightly more likely to develop tuberculosis. The same inflammatory cytokines that seem to have attacked their joints have also protected them from TB.
One of the most fascinating questions in immunology today is why not everyone suffers from asthma. After all, the air we breathe is full of germs, viruses and other irritants. Since millions of patients with asthma are hypersensitive to everyday substances such as cat dander or pollen, it stands to reason that their allergic reactions trigger chronic inflammation in their bodies. However, people who develop asthma as adults often do not have allergies. Doctors still don't know what causes their disease, but the signs of inflammation are just as present in their lungs.
Many treatments for asthma aim to control inflammation without being able to cure the disease from the ground up. Either the inflammation hypothesis is not entirely correct, or the drugs used to treat inflammation are not completely effective.
Gold is also a strong anti-inflammatory metal; the gold ions are absorbed by the mast cells and macrophages of the immune system, where they inhibit the formation of certain pro-inflammatory cytokines. It appears that other anti-inflammatory measures, such as the regular intake of high doses of omega-3 fats, vitamin D3, curcumin, resveratrol or OPC, to name just a few examples, are able to support the anti-inflammatory effect of gold.
Doctors everywhere are finding evidence that inflammation plays a greater role in chronic diseases than previously thought. However, this does not necessarily mean that they know what to do about it. This could soon change. Researchers are looking beyond acetylsalicylic acid and other multi-purpose drugs to find dietary supplements that block inflammation more precisely. However, much more basic research into the nature of inflammation needs to be conducted before scientists can understand how best to limit the damage caused by chronic disease.
In the meantime, there are things we can all do to curb our inflammatory foci. Some of the tips may sound awfully familiar and mundane, but we have new reasons to follow them. Losing weight stimulates fat cells to produce - remember them? - fewer harmful cytokines. Regular exercise, 30 minutes a day most days of the week. Flossing fights gum disease, another source of chronic inflammation. Fruit, vegetables and fish are full of substances that deactivate free radicals.
So if you want to stop the inflammatory processes in your body, get up from the couch, walk to the weekly market to buy fresh vegetables and make sure you don't catch any splinters on the way!
