|September 26, 2014 08:45
What does the collapse of a toe or a splinter in a finger with the risk of developing Alzheimer's disease, suffering a heart attack or succumbing to colon cancer ?.
More than you think. As scientists delve into the root causes of these and other diseases, they are starting to see links to a mechanism of immune defense, called inflammation - the same biological process that turns the tissue around a wound in red and causes swelling in the injured toe. If they are right - and evidence is beginning to be very solid - could radically change the concept of doctors what ails us. It could also be a bonanza for pharmaceutical companies looking for new ways to stay healthy.
Most of the time, inflammation is a lifesaver that enables our bodies to fend off various disease-causing bacteria, viruses and parasites. (Yes, even in the modern world, we are constantly bombarded by pathogens.) In the instant any of these potentially deadly microbes slide in the body, inflammation leads a defensive attack that claimed the invaders and any tissue that has have infected. Then, just as quickly, the healing process and decreases comienza.0
Occasionally, however, all that vehement production does not close at the right time. Sometimes the problem is a genetic predisposition, other times, actions such as smoking or high blood pressure do keep the process going. In any case, the inflammation becomes chronic rather than transient. When that happens, the body turns on itself - like a stubborn child who cannot resist touching a wound - with consequences that seem to underlie a wide variety of diseases.
Suddenly, inflammation has become one of the hottest areas of medical research. Not a week passes without the publication of another study that discovers a new form of chronic inflammation that damages the body. Cholesterol deposits in the coronary arteries becomes unstable, leading to heart attacks and potentially even strokes. Lose nerve cells in the brains of Alzheimer's victims. It can even enhance the proliferation of abnormal cells and facilitate its transformation into cancer.
In other words, chronic inflammation may be the engine that drives many of the most feared diseases of middle and old age.
This concept is very interesting because it suggests a new and possibly much simpler to protect themselves from disease. Instead of different treatments, for example, heart disease, Alzheimer's disease and colon cancer, inflammation-reducing may be a single remedy, which prevents the three. Chronic inflammation also fascinates scientists because it indicates that our body can, from an evolutionary perspective, become a victim of its own success. "We have evolved as a species because of our ability to fight microbial invaders," says Dr. Peter Libby, chief of cardiovascular medicine at Brigham and Women's Hospital in Boston. "The strategies our bodies used for survival were important in a time when there were no plants to purify water, as well as no sewage systems had to protect ourselves.
But now that we are living longer, these inflammatory strategies are more likely to slip out of our control. To make matters worse, it seems that many of the attributes of a Western lifestyle - such as a diet high in sugars and saturated fats, accompanied by little or no exercise - also make it easier for the body to come in inflammation.
The new view of inflammation is changing the way some scientists do medical research. "Virtually all our efforts in R & D (research and development) is focusing on inflammation and cancer," says Dr. Robert Tepper, president of research and development at Millennium Pharmaceuticals in Cambridge, Massachusetts.
In medical schools in the United States, cardiologists, rheumatologists, oncologists, allergists and neurologists are communicating to each other - and are discovering they are looking at the same thing. The speed with which researchers are jumping on the bandwagon of inflammation is awesome. A few years ago, "nobody was interested in these things," says Dr. Paul Ridker, a cardiologist at Brigham and Women's Hospital who has done pioneering work in the area. "Now the whole field of inflammation research is about to explode."
To better understand that all this is stirring, it helps to know a little about the basic immune response. A cascade of events is triggered when the body is subjected to trauma or injury. As soon as a sliver enters a finger, for example, specialized cells throughout the body sentinel alert the immune system to the presence of any bacteria that may have arrived. Some of these cells called mast cells release a chemical histamine which causes leaking capillaries. This allows small amounts of plasma leakage, slowing down invading bacteria, and prepares the way for other faraway immune defenders to easily enter the fight.
Meanwhile, another group of sentinels, called macrophages, begin an immediate counterattack and release more chemicals, called cytokines, which gives more signal boosters. Soon, wave after wave of immune cells flood the site, there is destruction of pathogens and damaged tissue alike - there is no removal of the wounded from the battlefield in this war. (No wonder the ancient Romans comparing inflammation under fire.) Doctors call this generalized response to virtually any type of attack, ..the innate immunity. Even bodies of animals as primitive as starfish defend themselves this way.
But higher organisms have also developed a defense system's precision guided helps direct and intensify the innate response and creates specialized antibodies, custom-made to target certain types of bacteria or viruses. This immunity is called evolutionary allowing pharmaceutical companies to develop vaccines against diseases like smallpox and influenza. Working together, the innate immune defenses and evolutionary fight pitched battles until all the invading germs are annihilated. In a final flurry of activity, a last wave of cytokines is released, the inflammatory process goes away, and healing begins.
Problems begin when, for one reason or another, the inflammatory process persists and becomes chronic, the final effects are varied and depend very much on where in the body the runaway reaction takes hold.
Among the first to recognize the broader implications were cardiologist who noticed that inflammation seems to play a key role in cardiovascular disease.
Is your heart at risk?
Not long ago, most doctors thought of heart attacks as primarily a plumbing problem.
Over the years, fatty deposits gradually build up inside of the main coronary arteries until they become so large that they cut off the supply of blood to a vital part of the heart. A complex molecule called LDL, the "bad" cholesterol is always the raw material for these deposits.
Clearly anyone with high LDL levels was at greater risk of developing heart disease.
There is only one problem with this explanation: sometimes it is totally wrong. In fact, half of all heart attacks occur in people with normal cholesterol levels. Not only that, with enhanced imaging techniques, doctors discovered, to his surprise, that the most dangerous platelets were not necessarily large. Something that had not yet been identified, was causing deposits were to burst, causing large clots that cut the coronary blood supply.
In the 1990s, Ridker became convinced that some kind of inflammatory reaction was responsible for the breakdown of platelets, and set about trying to prove it. To test his hunch, Ridker needed a simple blood test that could serve as a marker of chronic inflammation. It was installed in 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, levels of CRP quickly shoot from less than 10 mg / L to 1,000 mg / L or more. But Ridker was more interested in the low CRP levels - less than 10 mg / L - found in healthy people and that indicated only a slightly elevated level of inflammation. In fact, the difference between normal and elevated is so small to be measured using a specially designed high-sensitivity assay of the PCR.
In 1997, Ridker and colleagues at Brigham and Women's has 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 those with .. lower CRP levels. Eventually, inflammation experts determined that having a CRP reading of 3.0 mg / L or higher can triple your risk of heart disease. The danger seems even greater in women than in men.
By contrast, people with very low levels of C-reactive protein, less than 0.5 mg / L, rarely have heart attacks.
Doctors still do not know for sure how inflammation can cause rupture of platelets. But they have a theory. As increases the level of LDL cholesterol in the blood, they speculate, some seep into the walls of the coronary arteries and stay there. Macrophages, alerted to the presence of something that does not belong, in and try to clean cholesterol. If, for any reason, the cytokine signals gradually increase, start the inflammatory process instead of going down, the plate becomes unstable.
"It's not about replacing cholesterol as a risk factor," Ridker says. "Cholesterol deposits, high blood pressure, smoking -. Contribute to the development of underlying plaques What makes inflammation is to contribute to the propensity for plaque rupture and cause a heart attack if there is only inflammation but no disease underlying heart, then .. no problem. "At this point, cardiologists are still not prepared to recommend to the general population be screened for inflammation levels. But there is a growing consensus that CRP should be measured in those with moderately elevated risk of developing cardiovascular disease. At least, a high CRP level might tip the balance in favor of more aggressive therapy with treatments - such as aspirin and statins - already known to work.
A new vision of Diabetes
Before Dr. Frederick Banting and his colleagues at the University of Toronto isolate insulin in the 1920s, doctors treated diabetes with high doses of salicylates, a group of aspirin-like compounds. (They were desperate and also tried morphine and heroin) Indeed, salicylate reduces sugar levels, but at a high price: side effects include a constant ringing in the ears, headaches and dizziness. Today's treatments for diabetes are much safer and generally work by replacing insulin, has increased its production or helping the body make more efficient use of the hormone. But researchers in recent years have turned to study the salicylate approach for new clues about how diabetes develops.
What we have discovered is a complex interplay between inflammation, insulin and fat - either in the diet or in large folds under the skin. (Indeed, fat cells behave a lot like immune cells, spewing inflammatory cytokines, especially as they gain weight.) How is that inflammation is set in this scenario - either as a cause or effect - it is not yet clear. But the fact that it occupies a central role .. is getting stronger. Dr. Steve Shoelson, a senior researcher at the Joslin Diabetes Center in Boston, has generated a strain of mice whose fat cells are factories inflammation. The mice become less efficient at using insulin and go on to develop diabetes. "We can play the full syndrome, only for inciting inflammation," Shoelson says.
This suggests that early intervention in the inflammatory process may reverse some of the effects of diabetes. Some of the drugs already used to treat the disorder, like metformin, may work because they also dampen the inflammatory response. In addition, preliminary research suggests that high CRP levels may indicate an increased risk of diabetes. But it is too early to say whether reducing CRP levels may actually keep diabetes at bay.
Cancer: The wound that never heals
Back in 1860, the renowned pathologist Rudolf Virchow speculated that cancerous tumors occur at the site of chronic inflammation. A century later, oncologists paid more attention to the role that different genetic mutations in promoting abnormal growths that eventually become malignant. Now researchers are exploring the possibility that mutation and inflammation mutually reinforcing processes, which if unchecked, can transform normal cells into potentially deadly tumors.
How can this happen?
One of the most potent weapons produced by macrophages and other inflammatory cells are called oxygen free radicals.
These highly reactive molecules destroy just about anything that crosses their path - particularly DNA. A glancing blow that damages but does not destroy a cell could lead to a genetic mutation that allows it to continue to grow and divide.
Abnormal growth still is not a tumor, says Lisa Coussens, a biologist at the Comprehensive Cancer Cancer Center at the University of California at San Francisco. But for the immune system, it is much like a wound that needs to be fixed. "When immune cells are called, they bring growth factors and a lot of proteins to call other inflammatory cells," Coussens explains. "Those things come and go heal, heal, heal." But rather than cure, what they do is' feeding, increase, providing ".
Sometimes the reason for the initial inflammatory cycle is obvious - as with chronic heartburn, which continually bathes the lining of the esophagus with the stomach acid, predisposing a person to esophageal cancer. Other times, is less clear. Scientists are exploring the role of cyclo-oxygenase 2 (COX-2) in the development of colon cancer enzyme called. COX-2 is another protein produced by the body during inflammation.
In recent years, researchers have shown that people who take daily doses of aspirin - recognizing COX2 blocks - are less prone to develop pre-cancerous growths called polyps. The problem with aspirin, however, is that it can also cause internal bleeding. Then, in 2000, researchers showed that Celebrex, other COX-2 is less likely to cause bleeding aspirin also reduces the number of polyps in the large intestine. Therefore, you should take Celebrex to prevent colon cancer? It is too early to say. It is clear that COX-2 is a factor in colon cancer. "But I do not think it's the only answer," says Ray DuBois, director of cancer prevention at the Cancer Center Vanderbilt-Ingram in Nashville, Tennessee "There are a lot of other components that need to be explored."
Aspirin for Alzheimer's disease?
When doctors treating Alzheimer's patients took a look closer at what seemed to be succumbing to the disease, they uncovered a tantalizing clue: those who were already taking anti-inflammatory drugs Disease arthritis or heart tends to develop the disorder later than those who were not taking anti-inflammatories.
Perhaps the immune system mistakenly saw the characteristic plaques and tangles that accumulate in the brains of Alzheimer's patients as damaged tissue that needed to be cleaned. If so, the inflammatory reaction that followed was doing more harm than good. Blocking with anti-inflammatories might limit, or at least delay, any damage to cognitive functions.
The most likely culprits this time around are the glial cells, whose function is to nurture and communicate with neurons. Researchers have discovered that glial cells can also act much like the skin mast cells, production of inflammatory cytokines that call other immune cells into action. "Glial cells are trying to return the brain to normal," explains Linda Van Eldik, a neurobiologist at Northwestern University Feinberg School of Medicine, Chicago. "But for some reason, in neurodegenerative diseases such as Alzheimer's, the process seems out of control. Against chronic glial activation, which leads to an inflammatory state is It."
It seems that some people are more sensitive to plaques and tangles (Plaques and tangles) than others. They may have a genetic predisposition. Or maybe a long-term bacterial infection, such as gingivitis or gum disease, keeps the internal activity and tip the balance toward chronic inflammation.
Preliminary research suggests that low-dose aspirin and fish oil capsules - two of which are known to reduce inflammatory cytokines - seem to reduce the risk of a person to Alzheimer's disease. Unfortunately, most of these preventive measures initiated long before neurological problems develop. "What we have learned with dementia is that it is very hard to improve what we already have," says Dr. Ernst Schaefer, a professor of medicine and nutrition Tuft's Friedman School of Nutrition in Boston. "But at least be possible to stabilize people and prevent disease."
When our body is also attacked.
Physicians who have more experience in the treatment of chronic inflammation are those who specialize in rheumatoid arthritis, multiple sclerosis, lupus and other autoimmune diseases.
For decades, these diseases have given the clearest example of a body at war with itself. But the spark that fuels their internal destruction does not come from excess cholesterol deposits or persistent bacterial infections. But in a strange twist of fate, the body supersophisticated guides and directs their immunological inflammatory mistakenly attack healthy cells in places like joints, nerves and connective tissue defenses.
In recent years, powerful drugs like Remicade and Enbrel, which specifically target the inflammatory cytokines, have worked wonders against rheumatoid arthritis and other autoimmune disorders. But as often happens in medicine, drugs have also created some problems. Patients taking REMICADE, for example, are slightly more likely to develop tuberculosis, as the same inflammatory cytokines that attacked their joints, also protect against tuberculosis.
Inflammation may be more of a problem in the early stages of autoimmune diseases such as multiple sclerosis. It eventually destroys tissue nerve damage becomes permanent. "The initial goal is to keep the immune response under control, but then you have to ask how to regenerate damaged tissue," says Dr. Stephen Reingold, vice president of research programs at the National Multiple Sclerosis Society. It could take decades solution.
Asthma without allergies?
One of the most intriguing questions in immunology today is why not everyone with asthma. After all, the air we breathe is full of germs, viruses and other irritants.
Since half of the 17 million Americans with asthma are hypersensitive to common substances like cat dander or pollen, it stands to reason that allergic reactions trigger the chronic inflammation in their bodies. However, people who develop adult asthma - one of the fastest growing segments of the population - often do not have allergies. Doctors still do not know what is driving their disease, but signs of inflammation are present in their lungs.
Many treatments for asthma are designed to control inflammation, but not cure the disease. "It may mean that the inflammatory hypothesis is not entirely correct or the drugs we use to treat inflammation are not fully potent," says Dr. Stephen Wasserman, an allergist at the University of California at San Diego. "There are a lot of gaps to fill even" Everywhere, in turn, doctors are finding evidence that inflammation plays an important role in chronic diseases that were thought to paper. But that does not necessarily mean they know what to do about it. "We are in a dilemma right now," says Dr. Gailen Marshall, an immunologist at the University of Texas Medical School at Houston.
"We are moving on the idea of becoming aware. But I can not really recommend specific treatments yet." That may change soon. Researchers are looking beyond aspirin and other multipurpose medications and go to experimental drugs that block inflammation more precisely. Any day now, Genentech is expecting a decision from the FDA on its drug for colon cancer, Avastin, which targets one of the growth factors released by the body as inflammation giving way to healing .
Millennium Pharmaceuticals is testing a different type of drug, called Velcade, which has already been approved for the treatment of multiple myeloma, lung cancer and other malignancies. But there is a sense that much more basic research on the nature of inflammation needs to be done before scientists to better understand how to limit the damage of chronic diseases.
Meanwhile, there are things we can all do to stop our inflammatory fires. Some of the advice may sound awfully familiar, but we have new reasons to keep going. Losing weight induces fat cells - remember them? - To produce fewer cytokines. So do regular exercise, 30 minutes a day most days of the week. Floss combat gum disease, another source of chronic inflammation. Fruits, vegetables and fish are full of substances that inactivate free radicals.
So if you want to stop inflammation, come down from the couch, put your head in the green market and try not to stub your toe on the way. - With reporting by Dan Cray / Los Angeles.