It should not come as a surprise that inflammation has been recognized for quite a long time. When the troglodyte banged his noggin against the low entrance to his cave home, he (or she, if we’re talking about a lady troglodyte) would develop a bump on his/her head. That bump was characterized by swelling, pain, heat, and redness. These were the four hallmark signs of inflammation, as described by the Roman physician, Aulus Cornelius Celsus, in the first century of the Common Era. In Latin, those were tumor (swelling), dolor (pain), calor (heat), and rubor (redness). Our word “inflammation” comes from the Latin “inflammare”, which mean “to set on fire.”

The famous Greek physician Aulus Galenus, better known as Galen, recognized that inflammation was the body’s way to attempt to heal an injury. Galen was the physician who treated the Roman emperor Marcus Aurelius, whose final years were plagued by a number of ailments. He had a better understanding of human anatomy than anyone until fairly recent times.

It wasn’t until the late 19th century that the physiology of inflammation came to be understood. The German scientist Rudolf Virchow observed that there was a fifth sign of inflammation, that being a loss of function in the affected area. Virchow described short-term inflammation as the body’s pathway to healing. The process of inflammation included the release of nutrients from damaged blood vessels and the attraction of a number of cells to the site of the injury or disease. Virchow also pointed out that inflammation could arise not only from external injury, but from pathologies affecting a person from within.

Virchow was perhaps the earliest scientist to surmise that while short-term inflammation was an aid to healing, long-term or chronic inflammation could result in damage to the affected person. This damage, in Virchow’s view, could include the development of cancer.

Our focus in this Doc Gumshoe installment will be on how acute inflammation can morph into chronic inflammation – how it develops, what factors might be the causes, the harms it brings, how it might be prevented, and how it might be able to be treated. However, the mechanism of chronic inflammation is essentially the same as that in acute inflammation, such as the inflammation resulting from an injury. The essential difference is that acute inflammation recedes as the injury heals, while chronic inflammation hangs around as long as the conditions that caused it remain unchanged. We might also call those conditions that lead to chronic inflammation “injuries,” and in a sense they are. Obesity, which as we’ll see is one of the conditions that bring on chronic inflammation, might be called an “injury” to our system. But while acute inflammation plays an important part in the healing of an injury, chronic inflammation (for example) does nothing to reduce obesity. So let’s take a look at the basic mechanism of acute inflammation.

You sustain an injury, not severe enough to send you to the emergency room, but definitely painful – let’s say you scraped your leg while climbing over a stone wall. The scrape only slightly broke the skin, and there was just a bit of bleeding, but the impact was painful. This event triggers a sequence of events, beginning with a considerable increase in local blood flow. The capillaries become more permeable, resulting in the build-up of fluid in the space in and around muscle and nerve fibers. A large number of cells of many different types are summoned to the area, and these immediately go to work to clean up the mess. Damaged tissue is devoured and carried off by macrophages and neutrophils, and the process of replacing dead cells with new cells begins. The entire area of the injury is walled off, so as to prevent the spread of any invading pathogens. And, yes, even though your skin was only slightly broken, pathogens certainly did enter. That’s because your skin (no matter how scrupulous you are about personal hygiene) is colonized by immense numbers of microbes of various kinds, especially staphylococci, which are primed to attack your cells. The inflammatory process is highly efficient at preventing the spread of staph infections that invade in that way. Once the infection has been contained by this walling-off process, your own immune system will wage war on the invading pathogens, and in most cases, your immune system will achieve victory in this war.

One could say that the reason the inflammatory process results in redness, swelling, heat, and pain, is that inflammation confines and concentrates the injury to a relatively small area, like waging an all-out war on a single small battlefield.  And, naturally, as in any war, there is collateral damage. If the inflammation occurs as a result of a bruise or a minor skin infection, the collateral damage will be minor. But if, on the other hand, inflammation occurs as a response to some type of internal disruption or as a reaction to certain types of stimuli, the collateral damage can be considerable. And, in some cases, inflammation seems to occur spontaneously, not in response to injury or a specific stimulus. In those cases, the inflammatory process in itself constitutes the disease.

The key word a couple of sentences above is “seems.” There is, of course, some factor that kicks off the inflammatory process. Inflammation does not occur spontaneously. But the main difference is that long-term chronic inflammation is not a response to a specific injury. The question, which we’ll attempt to answer later, is what are these factors that lead to chronic inflammation.

First, let’s take a closer look at the acute inflammatory process.

Acute inflammation and the chief players

Whenever there is damage to any part of our bodies – whether external or internal, from trauma, something harmful that we ingested, an invading pathogen – our immune system dispatches inflammatory cells to destroy the invaders, get rid of whatever harmful substances, heal the tissues, and restore our bodies to a state of balance.

The first responders are mast cells, which are present in our tissue throughout our bodies. The mast cells send signals which trigger the release of histamine, a chemical that has an immediate effect on the circulatory system, in particular the omnipresent capillaries. The capillaries immediately contract, to minimize blood loss. But the secondary reaction is dilation. The capillaries widen to bring more blood to the area of the injury. If the injury is on the surface of our bodies, it is this increase in blood flow that creates swelling, redness, and heat.

The increased blood flow has an immediate benefit, which is that it carries more oxygen to the injury, which is an aid in the healing process. Another immediate effect, which is a mixed blessing, is that several substances that increase the perception of pain are carried to the area. These include kinins such as bradykinin and cytokines. But in a way the increased perception of pain is a blessing. Instead of touching the injury, we tend to avoid touching it, which avoids further injury and infection.

An effect of the action of the histamine is that the endothelial cells that line the inner surface of the capillaries contract, so that there is more space between the cells. This permits other inflammatory agents to pass through the capillaries and reach the affected area. These include clotting factors and white blood cells, termed leukocytes.

The damaged tissue releases substances called chemotaxins, which in turn summon other types of white blood cells, including neutrophils and phagocytes. These cells attack and destroy harmful invaders. The phagocytes in particular perform the crucial task of engulfing and consuming pathogens.

The battle between pathogens and the immune agents leaves a lot of residue on the battlefield – dead white blood cells, a lot of fluid that has been drawn to the area, and dead microbes. This mess is what is called pus. Eventually the immune system sends out another phalanx, this time to clean up the battlefield. The cells that do this dirty work are called macrophages. Mostly the macrophages do a pretty good job, but sometimes the pus collects in little pockets, creating what is called an abscess.

After the battle is over, the immune system sends in specialized molecules to repair the damage and get the healing process underway. These molecules are called “pro-resolving mediators.” They work to taper down the inflammatory process.

Cases of acute inflammation resolve fairly quickly, sometimes in just a few hours and usually within a few days.

An easy road map to the immune system

The first line of defense is our skin. It’s a physical obstacle to invaders, and not only is it too tough for most invaders (I exclude mosquito bites and rose thorns), but its surface, being slightly acidic, is not friendly to most microbes. In addition to which, our skin is populated by bacteria which are hostile to invading bacteria. However, there are openings in this protective coating. It may be safe to touch a surface contaminated with hostile germs, but don’t rub your eyes – or any other part that is not well-protected by your skin. If you should happen to get some nasty pathogen in your mouth and it goes down your esophagus, chances are your stomach acids will kill it.

We were born with some immunity, usually called “innate immunity.” Newborns have phagocytes very close to the surface of their skins, and these cells can engulf invading germs, tear them apart and excrete them. When phagocytes swallow an invader, they display little pieces of the invader on their surface. This sets into motion the process of adaptive immunity, as B-cells transmit information about the invader’s pattern to killer T-cells, which will locate and attack any related invaders.

Another line of defense consists of proteins within our cells that can be released when a cell detects the presence of a possibly hostile virus. These proteins are called interferons. They bind to the surface of our cells and prevent invading viruses from attaching to those cells.

If innate immunity doesn’t do the job in the first few days after the injury, adaptive immunity comes into play. Adaptive immunity develops more slowly, but it is quite a bit more precise. This form of immunity has the capacity to recognize and remember pathogens for a long, long time. For example, once you have had a disease like chicken pox, those memory B-cells will stay in your system, and if you are exposed to that same varicella zoster virus that caused chicken pox in the first place, the B-cells will very quickly call out reinforcement, which (as we have said) are killer T-cells.

Another form of adaptive immunity is the antibody response. Antibodies continue to be present in your blood and body fluids, although they do not last nearly as long as the B-cell / T-cell combo. There are several flavors of T-cells besides the killers. These include T-cells that work to regulate the immune process and attempt to prevent it from continuing unchecked and damaging the body’s tissues, and also memory T-cells that work more or less like B-cells, remembering the distinguishing features of particular pathogens.

The immune system and inflammation

The discussion of acute inflammation above is chock-full of the names of cells and other agents that participate in the process – mast cells, histamines, bradykinins, cytokines, interleukins, endothelial cells, leukocytes, chemotaxins, neutrophils, phagocytes, macrophages, pro-resolving mediators, B-cells, T-cells, lymphokines, caspases, and many, many others. There will not be a quiz in which you are required to remember all those names and what they do. The point is that the immune system is a highly complex process, and it employs a huge number of agents, some of which are direct mediators of inflammation, in order to carry out its mission of keeping the host safe from infection and injury. (The word “mediators” here means that they are they are the agents that turn on the switches on those immune mechanisms, not that they act as mediators between two opposing causes.)

These various cells are vital participants in the immune process and may not directly lead to inflammation. It is the immune process as a whole that can lead to inflammation. For example, a number of factors also stimulate generation of granulocytes and monocytes by the bone marrow; these include tumor necrosis factor (TNF), which is one of the drivers of rheumatoid arthritis (RA).

A large category of inflammatory mediators are classified as cytokines, although by no means are all cytokines pro-inflammatory. I attended a meeting of the American College of Rheumatology where a scientist attempted to present an overview of the cytokines. Rheumatology, by the way, is the branch of medicine that studies inflammatory diseases; “rheum” being the old-timey word for the wet discharge from the eyes or nose, and also for the substance that accumulates in areas affected by inflammation. Thus “rheumatism” was the word for what is now called arthritis. Rheumatologists are the medical specialists that also treat other diseases where the immune system turns against the host, such as inflammatory bowel disease (IBD), Crohn’s disease, psoriasis, and ankylosing spondylitis. These are usually classified under the heading “autoimmune diseases.”

The presenter began with a simple slide that mostly showed the interleukins, a well-studied group of cytokines, some of which are clearly pro-inflammatory and some, quite the contrary, are anti-inflammatory. There were about twenty cytokines on that slide. He then went on to show a slide with about one hundred cytokines on it, in different groups, in boxes connected by arrows. Then he put a slide on the screen that had so many cytokines on it that no one could possibly read one single name. He admitted that it was possible and even likely that many of the cytokines listed on the slide were identical. For example, a scientist in a lab in Cambridge might have identified this one, and a scientist in Palo Alto might have identified that one, and they were the same cytokine, but no one had spotted it. The audience erupted in laughter.

Consequences of inflammation beyond the known autoimmune diseases

The evidence for this has been around for about 30 years. Before that, arthritis, at least, was thought to be a relatively benign disease. Old people with arthritis could hobble around with canes, or in the most severe cases, could get around on wheelchairs, but arthritis, whether osteoarthritis or autoimmune rheumatoid arthritis, didn’t kill people.

Rheumatoid arthritis, as the name indicates, is intrinsically an inflammatory disease. What happens in rheumatoid arthritis (RA) is that the tissue between the bones in our joints is targeted by a cytokine termed tumor necrosis factor, which has a number of roles, including (as the name indicates) attacking and destroying harmful tumors. But this usually beneficial cytokine can go astray, and when the material in the joint space is destroyed, the joints grind on each other. To try to offset the damage, our bodies dispatch a great deal of fluid to the area – what is termed “rheum” – producing inflammation and its accompanying symptoms.

The notion that RA didn’t kill people began to be exploded in 1984 when a rheumatologist named Theodore Pincus caused a considerable stir at an ACR meeting when he reported that in a group of 75 patients with RA who had been tracked for 9 years, the mortality rate was about the same as in patients with heart disease blocking three coronary arteries – i.e., really severe disease. By the mid 1990s, there were lots of data showing that, in fact, rheumatoid arthritis did kill people – or, at least, that patients with rheumatoid arthritis were more than twice as likely to die as people of the same age in the general population.

But how on earth did this disease, which apparently affected only the joints, result in fatalities? It had been observed that persons with RA tended to have higher incidences of cardiovascular disease than those without RA, and it was conjectured that a possible reason for this was that RA patients were much more limited in terms of physical activity. In the view of some, lack of exercise was the culprit that was consigning RA patients to a premature death.

That line of reasoning appears to be sound, up to a point, in that physical activity certainly does contribute to cardiovascular health, and inactivity does the opposite. But several kinds of data began to appear about 20 years ago that suggested a different mechanism. Some of the data was statistical and some was the result of close scientific observation.

The mid-1990s, you will perhaps remember, were an era in which elevated cholesterol had been confirmed, in the view of most cardiologists, as the essential cause of coronary artery disease. It had been established that atherosclerosis consisted of cholesterol deposits in the arteries, and the recent 4S trial had conclusively shown that in patients with heart disease, statin treatment greatly reduced the incidence of significant cardiac events such as heart attacks and obstruction of coronary arteries requiring revascularization. In other words, problem solved: cholesterol is the culprit.

Some data got in the way of this unitary explanation. One was that a certain number of individuals who had “normal” cholesterol levels nonetheless experienced the same kind of cardiac events. Dr Paul Ridker, a cardiologist at Brigham and Women’s hospital and Harvard Medical School, found that these persons, who did not have cholesterol at levels that had been associated with heart disease, did have elevated levels of C-reactive protein (CRP), which for more than 80 years has been known to be associated with generalized inflammation.

At about the same time, another Brigham and Women’s/ Harvard cardiologist, Dr Peter Libby, learned that cholesterol didn’t just swim around in the bloodstream. It actually worked its way into the arterial wall. This appeared to constitute a kind of insult to the arterial wall and provoked an inflammatory response, which in turn resulted in the formation of blood clots. It was these blood clots that, at least in some cases, blocked coronary arteries, causing heart attacks, and also blocked cerebral arteries, causing strokes. Peter Libby coined the term “vulnerable plaque” for plaque affected by inflammation that was prone to clot formation.

In 2017 Libby and Ridker published the results of a trial which changed the way chronic inflammation is recognized as a causative factor in a number of illnesses and conditions that have major impact on our lives. The trial, called CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), involved more than 10,000 subjects in 39 countries. It was initially designed to determine whether an anti-inflammatory drug by itself could lower the rates of cardiovascular disease, without at the same time lowering the levels of cholesterol, as the statin drugs do. (Ridker PM. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017 Sep 21;377(12):1119-1131.)

The answer was an emphatic yes. The trial revealed further results of great interest. Other outcome measures in the trial also showed that canakinumab, an anti-inflammatory drug, had unexpected therapeutic results in other areas. For example, lung cancer rates in the study population treated with the drug were 77% lower than in the placebo subjects, and rates of arthritis and gout also fell substantially.

The specific target of canakinumab is interleukin 1β, which is a known cause of inflammation and a generator of C-reactive protein (CRP), a marker of inflammation. Canakinumab (Ilaris, from Novartis) is indicated for patients 4 years of age and older to treat familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS), which are both part of the cryopyrin-associated periodic syndromes (CAPS). These are very rare hereditary inflammatory diseases, mostly emerging in very young children.

The CANTOS trial was the culmination of about three decades of research on that interleukin, IL-1, which had been discovered in 1977. Researchers had learned that when the endothelial linings of arteries dilate, they leak proteins. One of those proteins was able to be isolated and cloned. They found that it could cause fevers in laboratory animals, thus it was called a pyrogen. It was named interleukin 1 (IL-1).

Ridker found that arterial walls not only responded to IL-1, they were able to secrete IL-1. He found that IL-1 amplified the signal at the site of the inflammatory process. This gave rise to the question – why should there be agents of inflammation that seem to spur the continuation of the inflammatory process past the point at which inflammation – acute inflammation – has served its purpose?

That question may be answered in evolutionary terms. At various points in the prehistory of our species there have been periods of extreme food shortage and mass starvation, likely caused by extended droughts. The survivors of those dire periods were likely to have had insulin resistance. Rather than metabolizing all or most of the food they ate, they stored a good part of it as fat, which got them through the worst of the drought. In today’s world, insulin resistance leads to diabetes, but at some past times, it was a survival characteristic. But while stored fat is a life-saving benefit in times of famine, it also harbors potentially damaging pro-inflammatory signaling molecules.

A second evolutionary factor is that having a hyperactive immune system was definitely a survival characteristic in an era when half the human population was wiped out by disease before age five. Now, when most children around the world survive the childhood diseases, thanks to widespread vaccination, the hyperactive immune system persists.

And a third evolutionary factor is trauma. To survive many forms of trauma, we have developed hypercoagulable blood. When you sustain a wound, your blood clots quickly. You don’t bleed to death. But that comes with drawbacks. In the present day, when we seldom encounter saber-toothed tigers or their ilk, our hypercoagulable blood can cause problems of many kinds – in our brains, our hearts, our circulatory system.

Hypercoagulable blood is not, strictly speaking, a factor in inflammation, although clotting is triggered by inflammation. But it aligns with one of the characteristics of inflammation, which is that physiologic reactions which are by and large immediately beneficial can, in the long term, become harmful.  An example is the IL-1β cell, which promotes adhesion. This stickiness is immediately useful in that it captures circulating immune cells and delivers them to damaged tissue. But in the long term that stickiness is the basis of the process that leads to atherosclerosis – plaque becoming attached to the lining of arteries. The endgame of a healthy immune response includes cleaning up the mess that the immune response leaves behind. The death of neutrophils as they are swept up and engulfed by macrophages is a signal of the resolution of an episode of acute inflammation. When this clean-up process does not occur, acute inflammation can morph into chronic inflammation.

Dr Rudolf Tanzi, a professor at Harvard Medical School, discovered several genes that were present in patients with Alzheimer’s disease. He says, “A significant portion of AD is caused by the inheritance of defective genes; specific gene mutations increase or decrease lifetime risk for AD. To date, four different genes have been implicated to play a role in familial Alzheimer’s disease (FAD). My lab has been involved with the discovery of three of these genes, including the amyloid beta protein precursor [APP], presenilin 1 [PSEN1], and presenilin 2 [PSEN2], which harbor mutations that cause a rare “early-onset” form of the disease with virtually 100% certainty, usually under 60 years old.” Tanzi identified the genes, but for several years he did not know what these genes actually did. Five years later, he and his associates determined that what the genes did was cause inflammation.

An associate, Dr Teresa Gomez-Isla at Mass General Hospital, has found some fairly strong evidence that even in persons whose brains have what many consider the hallmark of Alzheimer’s, amyloid beta plaques and neurofibrillary tangles, if they do not have those genes identified by Tanzi, they do not have Alzheimer’s. This suggests that an ultimate root cause of Alzheimer’s is chronic inflammation. Gomez-Isla’s finding neatly parallels the pathological interaction between arterial plaques and inflammation in atherosclerosis.

The diseases that chronic inflammation is linked with are the diseases that tend to affect us as we age – diabetes, cardiovascular disease, stroke, Alzheimer’s, cancer. Unfortunately, these maladies frequently co-exist as clusters.

Besides these diseases, chronic inflammation is linked with a great many other diseases, including multiple sclerosis, Parkinson’s, asthma, chronic obstructive pulmonary disease, chronic hepatitis, several kidney diseases, macular degeneration, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, and arthritis.

Of the factors that lead to chronic inflammation, the one that is most able to be addressed in an effort to prevent inflammation is the accumulation of excess body fat. Adipose tissue is laced with immune cells, which become more abundant with weight gain. Fat cells can secrete alarm signals that summon white blood cells. These fat cells – adipocytes – are more than 90% triglyceride. If the thin cell wall ruptures, an inflammatory response follows. And fat cells rupture easily, because, as they attempt to store more and more triglycerides, the cell wall stretches beyond its capacity to stretch, and the cell ruptures and starts to spill its contents, which can be toxic. The immune response summons the clean-up crew, but the macrophages themselves may burst as they engorge themselves with the fat cells’ contents. Obese individuals may be in a constant state of chronic stress and inflammation, because their input vastly exceeds their consumption.

Ways to minimize the effects of chronic inflammation

The first question anyone will ask is, “What about those anti-inflammatory drugs? Aren’t NSAIDS like ibuprofen supposed to be anti-inflammatory?” Yes, NSAIDS are non-steroidal anti-inflammatory drugs. What they do is block a particular enzyme, cyclooxygenase, which is required for the conversion of arachidonic acid into molecules that lead to inflammation. But while NSAIDS are quite effective when taken to address a symptom of acute inflammation, such as localized aches and pains, long-term use of NSAIDS comes with its own suite of perils, such as bleeding in the intestinal tract.

Aspirin works in a different way. It doesn’t block inflammatory signals outright, but it does attenuate them, and it has mild anticoagulant properties that are beneficial in atherosclerosis, although GI bleeding can also be an issue.

As you may have concluded by now, diet is probably an effective and safe way to dial down the inflammatory process. Here’s a summary of what Harvard Health Publishing calls “A Quick Start Guide to Anti-Inflammatory Eating.”

• Avoid ultra-processed food, which includes just about anything that comes pre-packaged. These foods tend to have minimal nutritional value and are high in added sugar, salt, and saturated fats. Examples: microwaveable dinners, hot dogs, chicken nuggets, dehydrated soups, sugary cereals, processed meats. Sugars, grains, and extra salt in ultra-processed foods can change the bacteria in the gut and damage the lining.
• To fight inflammation, go for whole, unprocessed foods with no added sugar: fruits, vegetables, whole grains, beans, lentils, fish, poultry, nuts, seeds, low-fat dairy, and olive oil.
• Antioxidants in brightly-colored fruits and vegetables – tomatoes, carrots, squash, broccoli, and berries of all sorts can lessen the effects of free radicals.
• Foods that are high in fiber, omega-3 fatty acids (salmon, mackerel, walnuts, etc), polyphenols (dark chocolate, coffee, tea, apples, citrus fruit, onions) and unsaturated fats (almonds, pecans, walnuts, pumpkin and sesame seeds, olive oil).

I must admit that I included that diet material with some reluctance. I am always struck that when it comes to instructing people about what they must and must not eat, the diet experts fall into the “everything is either forbidden or compulsory” turn of mind. My own inclination is to stay comfortably within the general area of the Mediterranean diet.

What does Doc Gumshoe take away from this discussion of inflammation? I would conclude that chronic inflammation affects most of us to some degree, and that it exacerbates quite a number of diseases and illnesses. The single modifiable factor that most favors chronic inflammation seems to be obesity. It seems clear that the tendency to eat more than we strictly need on a day-to-day basis has been with us from the dawn of time. It was a survival characteristic a hundred thousand years ago, but it’s probably not a survival characteristic any more, at least in the more fortunate parts of the world.

There are contributing factors to most of the diseases associated with inflammation. It’s clear that atherosclerosis is an inflammatory disease, but it wouldn’t take place unless there was an abundance of cholesterol in the arterial blood, and cholesterol really is transported by those particles of low density lipoprotein, so inflammation by itself is not the sole villain. Rheumatoid arthritis is an inflammatory disease, but there is something else in the mix that causes those tumor necrosis factor molecules to attack the surfaces of our joints. What’s interesting about chronic inflammation is that it is a part of so many of our earthly afflictions, and that we do have the means to minimize its impact. That doesn’t mean that we all need to forego all our earthly pleasures, but that we do have a choice.

* * * * * * * *

A question that I was unable to answer in a previous Doc Gumshoe commentary had to do with a treatment that had been “hailed by the Nobel Committee as the Holy Grail of medicine.” Since then, my in-box has been getting peppered with pop-up ads that claim that Ben Carson, a Nobel Prize winner, has developed a treatment called sometimes “Vigor Smart IQ” and sometimes “Magic Mushroom Brain.” Well, sorry, but Ben Carson is NOT a Nobel Prize winner. I know nothing about that treatment, whatever it’s called, but the way it’s being touted marks it as a fraud. I’m not biting. But do keep the questions and comments coming.

However, there’s new news both on COVID-19 and monkeypox, and other interesting news as well. Thanks & best to all! Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers once or twice a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]