When our troglodyte ancestors cracked their noggins on the low-hanging entrances to their cave dwellings, they surely experienced the pain and swelling that we experience when we unwittingly bang our skulls against some object or structure that we had failed to notice. A few hundred thousand years later, when Porthos hit his head on a stone support in a tunnel that he and his companions were trying to make their way through, Aramis commented that the reason for the swelling that quickly resulted was that Porthos’s large brain was bulging through a crack in his skull. This was a joke, of course, since Porthos was not noted for a large brain. A large heart, yes, and a large, strong body, but not a large brain (Athos and D’Artagnan, by the way, did not comment).

We’re talking about inflammation, of course. The last time Doc Gumshoe addressed inflammation was in a piece that posted on August 9, 2022. It’s worth taking another look at inflammation, because recent research has pinpointed an interleukin that is part of the inflammatory process, which can lead to cancer, and also identified a drug that can address this interleukin and halt the inflammatory process.

Before we get to that, let’s review what we know about inflammation in general. The central concept is that inflammation is both helpful and harmful. The bump on Porthos’s head was caused by the influx of fluids that helped the wound heal. However, inflammation can also be a chronic condition, which brings with it a parcel of troubles.

Porthos’s 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.

Here’s a look at the inflammatory process. 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.

These are the classic symptoms of acute inflammation, beyond the traditional signs of redness, swelling, heat, and pain:

• Fatigue and lack of energy
• Depression and anxiety
• Muscle aches and joint pain
• Constipation, diarrhea, and GI complaints
• Change in weight or appetite
• Headaches
• Fuzzy mental state

The inflammatory process is the same, whether we’re talking about acute inflammation or chronic inflammation. That is to say, the process is the same, but the results of the process are entirely different.

Chronic inflammation

In contrast with acute inflammation, chronic inflammation – as the term implies – is not short-lived. And, also in contrast with acute inflammation, it is rarely helpful. Although it may begin with the same cellular activity as acute inflammation, it morphs into a lingering state that persists for months or years. The body sounds the alarm and emergency help arrives, but the threat never recedes and the fire continues to burn.

Chronic inflammation is a slower, but more insidious process than acute inflammation, and it has been linked to a number of serious diseases, including heart disease, stroke, type 2 diabetes, cancer, Alzheimer’s disease, and arthritis.

In chronic inflammation, what may have started as the solution – for example, as a way to rid the body of a dangerous invader – instead becomes the problem. Chronically inflamed tissues continue to send out alarm signals that trigger the body’s immune response long after the threat has subsided.

When white blood cells heed the call and arrive at the scene, they sometimes attack healthy tissues and organs, further amplifying the response and setting the stage for a persistent inflammatory state.

As a result of this process, more tissues are attacked and destroyed instead of entering a healing process. For example, when pro-inflammatory cells remain in the blood vessels, they promote the build-up and deposition of sticky arterial plaque. This is the same plaque that contributes to cardiovascular diseases. But our immune system detects this arterial plaque as a foreign invader, and deploys yet another army of first responders.

Chronic inflammation can develop in any of several ways. One possible avenue is that the body is unable to rid itself of an offending substance, whether it is a pathogen, some kind of irritant, or a dangerous chemical toxin. Our immune system is usually highly efficient at eliminating invaders of any stripe, but sometimes pathogens resist even our best defenses and conceal themselves in our tissues, repeatedly provoking the inflammatory response. And chronic inflammation may be the result of the body’s failure to effectively break down and remove damaging chemicals.

The possibility of autoimmune disorders can also cause chronic inflammation, even if no actual autoimmune disorder is present. The list of possible autoimmune disorders is lengthy and probably a bit beside the point in this discussion, but here it is in part for your reference: Addison disease, Celiac disease, sprue, Graves disease, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, multiple sclerosis, Myasthenia gravis, pernicious anemia, reactive arthritis, rheumatoid arthritis, Sjögren syndrome, lupus, and type I diabetes.

When the body suspects the presence of any of these autoimmune diseases, the immune system goes into “threat mode”. In an autoimmune disorder, the immune system seems to become overly sensitized to the body’s own healthy cells and tissue. It reacts against the joints, intestines, or other organs and tissues as if they were dangerous. As the inflammatory response continues, it damages the body instead of healing it.

Mediators of inflammation

The very word “mediators” in that context is a bit confusing, at least to the non-medical reader. Most people think of mediators as the folks who try to resolve differences between two warring parties, like the opposite sides of a lawsuit or labor unions versus management. In medical terminology, the mediators are the agents that trigger the response, period. There is no give-and-take.

The numbers of inflammatory mediators are legion. They can be relatively simple molecules or living cells. Some of the ones whose names most people will recognize include histamines, serotonin, prostaglandins, bradykinins, a number of cells carried in the bloodstream such as macrophages and neutrophils, B-cells, T-cells, lymphokines, caspases, and many, many others. 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 of the immune system, such as inflammatory bowel disease (IBD), Crohn’s disease, psoriasis, and ankylosing spondylitis.

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 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.

I put in that little story not to make the Gumshoe Tribe erupt in laughter, but to illustrate how the research goes. Scientists see something going on, and they investigate all the different particles – individual molecules or cells – and try to determine what roles they are playing in what’s going on. It’s easy to see what macrophages are doing. They are huge (comparatively) and one can actually watch them in action. Besides cleaning up the mess that occurs when pathogens invade and create an infection, macrophages are capable of pumping out many different small molecules that also contribute to the inflammatory process.

The small molecules such as cytokines are a different matter. Scientists detect the presence of such a molecule in association with an inflammatory process, and then they try to figure out what its role might be, if any. Cytokines do not engulf and gobble up bacteria or cells. Instead, they may interact chemically with receptors on the surface of these bodies, or they may pass through openings in their coating. These actions depend on the precise shape of the molecules and on their binding properties. Sometimes a molecule fits neatly into receptors on the surface of a cell, thereby inactivating the receptor. The activity of some of these molecules may be conceptually simple, but detecting and understanding that activity is far from simple.

Consequences of inflammation beyond the known autoimmune diseases

(The following few paragraphs get more complex. If you feel like skipping ahead, don’t worry about it – there won’t be a quiz. But the subject is indeed complicated, as chronic inflammation affects more of our physiology.)

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, wasn’t thought to kill people.

That notion 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. Since the 4S trial, the benefit of statin treatment in persons with elevated cholesterol who have not developed any form of heart disease has been questioned, but statin treatment continues to be strongly supported in persons with heart disease.

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 as people with markedly elevated cholesterol. 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, 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.

(Now, lest the above information confirm the views of those who claim that it’s not cholesterol but inflammation that is the archvillain, let me insert a modest demurral, viz, lots of factors besides inflammation can cause the formation of blood clots. Blood tends to clot all on its own, and conditions such as atrial fibrillation, in which blood pools in the heart antechambers, or venous thrombosis, favor the formation of blood clots.)

Paul Ridker followed up his discovery about CRP with a study in which it was shown that treatment with statins not only lowered cholesterol levels, but also lowered levels of this inflammation marker. And in 2008, Ridker presented the results of the JUPITER trial at the New Orleans meeting of the American Heart Association. (Ridker P et al. New Engl J Med 2008;359:2195-2207). This large trial (17,802 subjects) compared two cohorts of persons, all of whom had normal cholesterol levels. One group of 8,901 subjects received 20 mg. of rosuvastatin daily, and the other, also 8,901, got the placebo. The primary endpoint was the incidence of signal cardiac events, consisting of nonfatal myocardial infarction, nonfatal stroke, unstable angina, or death from cardiovascular causes. Subjects receiving rosuvastatin experienced 142 such events, while those on placebo experienced 251 events. Although the reduction was small in terms of absolute risk – about 1.2% – it was considered highly significant, both statistically and in terms of implications for treatment. As a result of these results, the trial was stopped after a bit less than two years because the sponsors considered it unethical to continue a large cohort of patients on placebo when significant benefit had been demonstrated in the treatment arm.

The subjects in the JUPITER trial had baseline LDL-cholesterol levels of 108 mg/dL and CRP levels of 4.2 – 4.3 mg/L. Those LDL levels are considered fairly desirable in patients with no established cardiac risk factors. However, CRP levels greater than 4.0 mg/L are now considered elevated and associated with significant risk.

The JUPITER trial cannot be said definitely to demonstrate that lowering CRP was the determining factor in reducing the numbers of signal cardiac events, but the 1.2% reduction in absolute risk suggests that CRP, an indicator of inflammation, increases the risk of signal cardiac events. Treatment with rosuvastatin not only reduced CRP from the baseline level to about 1.8 mg/L, but also lowered the LDL levels from a pretreatment 108 mg/dL to 55 mg/dL, so the benefit may have in part been due to the LDL reduction. But the reduction in that marker of inflammation was certainly an eye-opener. At the AHA meeting, Steven Nissen of the Cleveland Clinic was quoted as follows: “…if a patient comes to me with normal LDL-cholesterol levels, I tell him to keep doing what he’s doing and to go about his business. Now, what happens when that same patient arrives in my office and I know his CRP is elevated? I know that treating him with intensive statins therapy, despite what the guidelines state, is going to cut his risk of cardiovascular morbidity and mortality in half.”

One conclusion to be drawn from this is that the statin, in this case rosuvastatin, addressed both elevated cholesterol and chronic inflammation. And it strongly suggests that elevated cholesterol is a manifestation of chronic inflammation.

How can inflammation be treated?

The first drug that had any effect on inflammation was the miracle drug aspirin. What we currently know as aspirin – acetyl salicylic acid – was introduced in 1897, but the precursor, willow bark, was used as a pain killer and a fever antagonist as long as three thousand years ago. Aspirin has four important properties. In addition to having significant pain-killing effects and lowering fever, aspirin reduces swelling, which means that it also addresses inflammation. A somewhat complicating effect of aspirin is that it inhibits the formation of blood clots. Since blood clots can lead to strokes and heart attacks, that can be a good thing. But blood clots are what stop bleeding, so aspirin is sometimes associated with episodes of internal bleeding.

A major breakthrough took place in 1963 with the introduction of indomethacin, a potent anti-inflammatory drug. Indomethacin was followed by several other non-steroidal anti-inflammatory drugs, now generally called NSAIDS, including ibuprofen (Advil, Motrin), and naproxen (Alleve). Those were followed by a number of other NSAIDS, which have somewhat different properties, but all work in more or less the same way, which is by inhibiting the action of prostaglandins, which are pain-producing hormones.

The NSAID designation distinguishes ibuprofen, naproxen and their similars from the corticosteroid class of drugs, which also effectively reduce inflammation. Corticosteroids include prednisone and the more potent methylprednisone. These drugs can ease symptoms of some inflammatory conditions such as arthritis, asthma, and some skin rashes. However, especially if used for extended periods, they can lead to a number of side effects and complications.

Inflammation and diet

What we eat affects every aspect of our lives, certainly including inflammation. Here’s a brief quote from a massive Harvard Health publication on the subject, directed to lay readers:

“Foods known to contribute to inflammation include white breads, cereals, white paste, and other products made with refined flours a well as white rice. Other offenders include soda, juices, cookies and other baked goods, butter, cheese, ice cream, coconut products, candy, salad dressing, jarred tomato sauces, and processed and cured meats.

To fight inflammation, go for whole, unprocessed foods with no added sugar, fruits, vegetables, whole grains, legumes (beans, lentils), fish, poultry, nuts seeds, a little bit of low-fat dairy, and olive oil.”

The recommendations go on in that vein for a bit, with no particular revelations. I’m certainly not taking exception to that guidance, but it strikes me as being the standard doctrine coming from the standard nutritionist. We might expect the same recommendations to reduce the risk of a number of diseases and conditions. They don’t specifically address inflammation.

A new and possibly promising development: Addressing inflammatory pain

This research, like much early-stage research, is taking place in mouse and computer model experiments. A new study, published in Nature Immunology (May 2024) identified thousands of molecular interactions — most not previously known — between pain-initiating neurons, or nociceptors, and different types of immune cells. These interactions could help explain why pain hypersensitivity sometimes occurs during inflammation — and could also help researchers resolve it.

The researchers used single-cell RNA sequencing to explore the crosstalk between those pain-initiating neurons and different types of immune cells in the skin, when the mice were exposed to three different types of pain triggers. Each trigger produced extensive changes in gene expression in the different immune cell types, especially macrophages. Some changes happened right away, while others took days to appear.

The key finding was that inflammatory pain isn’t a single entity. Each of the three inflammatory pain sources the researchers tested produced distinct networks of interactions between nociceptors and immune cells. That means all three have different mechanisms driving pain.

In addition to mechanisms driving pain, the study found that immune cells made and secreted more of a factor called thrombospondin1 (TSP1) in all three pain models. TSP1 had never been studied in pain or in the peripheral nervous system before. Treating nociceptors with TSP1 suppressed their pain signaling. The researchers think that TSP1 may help restore balance, easing pain when pain is no longer needed as an alert system.

The researchers plan further studies of TSP1 and the CD47 receptor it acts on to see if they can develop a pain treatment. They also plan to use their discovery platform to find new factors that cause or help resolve pain.

And another possibly promising development

A study, published in the May issue of Nature Communications, reported that in mice, a commonly-used cholesterol-lowering drug, pitavasatin, suppressed environmentally-induced inflammation in the skin and the pancreas, and prevented the development of inflammation-related pancreatic cancers.

A team of investigators from Harvard-affiliated Mass General Cancer Center showed that environmental toxins, such as those caused by exposure to allergens and chemical irritants, create a cascade effect that stimulates inflammation in the skin and pancreas. That degree of inflammation, when chronic, can result in cancer. Their findings suggest that using statins to suppress this pathway may have a protective effect.

The study’s senior author, Shawn Demehri, observed that chronic inflammation is a major cause of cancer worldwide. He said, “We investigated the mechanism by which environmental toxins drive the initiation of cancer-prone chronic inflammation in the skin and pancreas. Furthermore, we examined safe and effective therapies to block this pathway in order to suppress chronic inflammation and its cancer aftermath.”

The study relied on cell lines, animal models, human tissue samples, and epidemiological data. The group’s cell-based experiments demonstrated that environmental toxins (such as exposure to allergens and chemical irritants) activate two connected signaling pathways called the TLR3/4 and TBK1-IRF3 pathways. This activation leads to the production of the interleukin-33 (IL-33) protein, which stimulates inflammation in the skin and pancreas that can contribute to the development of cancer.

When they screened a library of U.S. Food and Drug Administration-approved drugs, the researchers found that pitavastatin effectively suppresses IL-33 expression by blocking the activation of the TBK1-IRF3 signaling pathway. In mice, pitavastatin suppressed environmentally-induced inflammation in the skin and pancreas and prevented development of inflammation-related pancreatic cancers.

In human pancreas tissue samples, IL-33 was overexpressed in samples from patients with chronic inflammation of the pancreas and pancreatic cancer compared with normal pancreatic tissue. Also, in analyses of electronic health records data on more than 200 million people across North America and Europe, use of pitavastatin was linked to a significantly reduced risk of chronic pancreatitis and pancreatic cancer.

The findings demonstrate that blocking IL-33 production with pitavastatin may be a safe and effective preventive strategy to suppress chronic inflammation and the subsequent development of certain cancers.

So the research goes on and progress continues, although sometimes at what seems painfully slowly. Yes, the research has to start off with computer models, Petri dishes, and small helpless laboratory animals before proceeding to actual human beings. But, however many years it takes to get through those necessary stages, if all goes well and according to plan, new treatment options become available for human beings. And we do definitely need new treatment options!

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Many thanks for all comments, and keep them coming! What are you curious about in the health-care area these days? I need clues about what to send your way. I do have a bit more to say about COVID, even though I’m eager to have the whole subject disappear into the mists of the past. But it keeps poking into the present.

Best to all, and stay well! 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.]