Inflammation
Fundamentals of Healing and Disease
Sentence:
Inflammation is a double-edged sword; necessary for healing from acute injury and disease, but its persistence is the basis for almost all acquired chronic disease.
Paragraphs:
Inflammation is a broad term that describes the body’s response to injury at a macro and micro scale. It is necessary for healing, but if it stays around for too long, leads to an array of diseases. The generally accepted responses to inflammation couldn’t be more wrong, though. We overtreat acute inflammation but ignore chronic inflammation and try to treat the secondary effects rather than the fundamental cause.
Examples of acute inflammation include localized swelling at the site of an injury, like a sprained ankle. It also includes systemic responses, like a fever when your body is fighting an infection. In both these cases, inflammation is helpful and necessary to help the body return to its normal state. Unnecessarily reducing inflammation with ice or medication delays healing.
Chronic inflammation is far less noticeable than acute, which is the primary reason it sneaks under the radar. It can be caused by persistent infections or injuries (osteoarthritis), prolonged exposure to irritants (air pollution or toxic chemicals (including those is our food, which some would argue includes sugar)), or autoimmune conditions. Not all causes of chronic inflammation are equal. Some are acquired through lifestyle with varying levels of genetic predisposition, and others (type 1 diabetes, hypothyroidism, and many autoimmune diseases) are essentially genetically predetermined.
While acute inflammation heals, prolonged inflammation injures, which in turn causes more inflammation in a vicious feedback cycle. If chronic inflammation is addressed at all, it’s usually by prescribing medicine to treat downstream symptoms rather than the root cause of the inflammation. The longer inflammation is allowed to persist, the harder it is to heal and reverse the damage caused.
Full essay and accompanying audio file are only available to paid subscribers.
Inflammation is the body’s response to a stressor. Whether it is a mechanical injury, like a cut or sprained ligament, or a molecular irritant from bacteria, virus, or harmful inorganic chemical, the initial response is one of inflammation. It is the first essential step in healing. It is also the starting point of essentially all chronic disease. It truly is a double-edged sword – beneficial in the short run, devastating if it stays around for too long.
On a cellular level, inflammation involves a complex series of events orchestrated by immune cells, blood vessels, and molecular signals to eliminate the cause of cell injury, clear out damaged cells and tissues, and initiate repair processes. Various cells in the area of the initial injury first detect if the stimulus is coming from damage (i.e. a mechanical injury) or a pathogen (i.e. virus/bacteria/chemical) through pattern recognition receptors on their surface. They then release a range of signaling molecules to initiate the appropriate response.
This response begins with changes in the blood vessels around the active site. The vessels dilate and become more permeable to allow more blood to reach the affected area. (Think of this as if a major disaster happened downtown in a large city, the roads in the area suddenly widened and added extra lanes so the emergency vehicles could reach the site faster.) This accounts for the cardinal signs of inflammation – redness and warmth due to increased blood flow and swelling due to increased fluid in the surrounding tissue. Immune cells also rush to the scene to destroy any encroaching pathogens and clean up dead cells and debris. The release of internal components from the damaged cells can indicate whether skin or other tissue repair needs to start.
Acute inflammation resolves as the body gains better control of the situation. The signaling molecules released in response to the injury naturally start to break down. Neutrophils, a type of immune cell that flock in large numbers to the site of inflammation, die off once their job is complete. Macrophages, another type of white blood cell, are initially activated to drive much of the inflammatory response. As the situation begins to resolve, they undergo a change in gene expression pattern and start signaling for everything to return to normal. This switch in macrophage behavior is important to prevent acute inflammation from becoming chronic.
In the case of an infection, if it is not controlled at the initial site of entry, the body employs further tactics to eliminate it. Everything involved in the initial inflammatory response that we’ve discussed so far is part of what’s called the innate, or non-specific, immune response. If it fails, though, the body’s response moves to becoming systemic (throughout the whole body) rather than local. This includes a fever and greater recruitment of immune cells.
The hypothalamus region in the brain acts as the body’s thermostat. Cytokines, or a type of molecular signal released during a widespread infection, act on the hypothalamus to raise the body’s temperature set point, resulting in a fever. The higher temperature slows down or inhibits replication of the invading pathogens while also increasing the efficiency of immune cells fighting the intruders.
In some cases, this systemic defense response can go too far and develop into SIRS (systemic inflammatory response syndrome) or sepsis. The primary difference between the two is simply that you call it sepsis if you have a known cause of infection and SIRS if you don’t. This out-of-control inflammatory response involves extremes of body temperature (high or low), rapid heart rate and breathing, and low blood pressure. This can then lead to confusion, dizziness, extreme fatigue and usually death if it’s not treated quickly. In the overwhelming majority of cases, though, your body responds to a widespread infection with a well-regulated systemic response that tilts the battlefield in favor of your body’s defense mechanisms fighting against intrusive microbes.
Acute, or short-term, inflammation is generally uncomfortable. Sprained ankles and cuts hurt. Fevers make you feel miserable. The natural response is to try and mitigate the pain and discomfort, but there is a trade-off between tolerating immediate discomfort and prolonging the healing process.
The typical treatment for a soft tissue injury is called the RICE protocol, or Rest, Ice, Compression, Elevation (which then evolved into more elaborate acronyms such as PRICE and POLICE, but more letters didn’t correlate with any more helpful knowledge). Soft tissue generally refers to either muscle, tendon, or ligament. As a reference point, muscle usually takes 2-4 weeks to heal, tendons 4-6 weeks, and ligaments 10-12. The difference in healing time is related to the amount of blood flow to each tissue type, with muscle generally having the most and ligaments having the least. The severity of the injury also plays a role, i.e. whether it’s a partial or complete tear.
Using a sprained ankle as an example, common knowledge says you should wrap it in an ACE bandage, put ice on it, and lay down on the couch with it propped up on some pillows. Ibuprofen every six to eight hours can help, too.
You should notice, though, that each of these interventions is intended to mute the body’s natural healing mechanisms. Why should you want to override your body’s attempts to fix itself? It’s often not a conscious intention, but rather a short-term attempt to reduce pain.
The RICE protocol was initially published in the “Sports Medicine Book” by Dr. Gabe Mirkin in 1978 (although it was commonly used before then). In 2015, in a stunning act of humility and self-awareness for a doctor, he recanted his long-standing recommendations1. Ice, rest, and NSAID use (i.e. ibuprofen) all likely prolong, rather than enhance, healing. The jury’s still out on whether compression and elevation make a difference one way or the other.
To be clear, icing an injury has been shown to effectively reduce pain, swelling, and bruising. The problem is that this delays the body’s healing response by limiting blood flow to the area, preventing the release of appropriate cell signaling to initiate healing, and can actually do further damage to the already-injured tissue (usually occurring if ice is left on for too long). And to be fair, the majority of the literature has shown that icing doesn’t help, not that it hurts. It does delay release of cell signaling molecules that initiate the healing process, so it likely slows healing to some degree, but muscles, tendons, and ligaments generally get better somewhere within their expected time frames (as listed at the start of this section).
So how does one most quickly heal from injury, then? If it’s severe enough to need surgery, then it needs surgery, but for everything else early movement is key. The injured tissue does need to be protected, at least for a short time. If you get hurt, stop exercising or playing immediately. Increasing the severity of the injury is only going to delay healing and return to activity. It’s reasonable to take the rest of the day off and start on rehab after 24 hours or so.
For rehab, aim move the injured tissue through the maximal possible range of motion without any load. Again, using an ankle as an example, if you can’t walk, sit on the couch and move it as far forward and back, side to side as you can. Over the next few days, aim to increase the range through which it can move and gradually increase the weight supported by the joint. If you absolutely have to put more load on the joint than is comfortable, for example you have to work, protect the joint with crutches or a brace and limit overstressing it as much as possible. Most studies have shown adhering to a home exercise program is equally effective as supervised physically therapy for rehabbing acute, single joint injuries. The fundamental principles are to gradually increase range of motion and load. One can quibble about various intricacies, but there’s not much more to it than that.
One quick note about rehabbing muscle or tendon injuries. As you are increasing load through exercise, focus on prolonging the eccentric phase of the movement, rather than the concentric phase. The eccentric phase is when the target muscle is elongating, rather than contracting. So with bicep curls, it’s when you’re letting the weight down, or with calf raises, it’s when you’re lowering your heels back down.
What about systemic inflammation, like a fever?
Again, your body’s natural response to an infection is to raise body temperature because it helps the immune system and inhibits the invading pathogens. The technical definition of a fever is 100.4o F or 38o C taken in the axillae (armpit). This threshold was initially established in the mid-1800s after Carl Wunderlich reviewed over a million temperature readings from more than 25,000 test subjects. More recent studies in patients presenting to the emergency room have confirmed having a temperature above 100.4o predicts an infection greater than 99% of the time. (There are various other arguments for and against this definition of fever, specifically lowering the temperature that defines a fever, but not constructive to the current topic.)
Like with localized inflammation, fevers are uncomfortable, and the natural response is to lower body temperature, often with an antipyretic (fever reducing) medication like ibuprofen or acetaminophen. Again, though, this intervention is directly muting the body’s natural attempt to defend itself.
Fever has been recognized as a response to infection since the 6th century BC. In the 5th century BC, Hippocrates explained fever by declaring it to be an excess of yellow bile, but it was considered as beneficial, because it meant the body would fight off disease. Fever was generally considered beneficial and necessary for healing until the 1800s. At that time medical personnel began to realize that it also indicated a risk of disease transmission, so feverish patients were isolated and treated to reduce fever. While the practice of isolation to prevent transmission was an important step forward, the pre-occupation with lowering fever was a step backward. (During the Spanish flu pandemic, the 1918 death spike was preceded by increased use of aspirin to toxic levels in a misguided attempt to reduce patient’s fevers.) The perception of fever as being a negative response has persisted until very recently.
Most of the research data again suggests that artificially lowering a fever doesn’t help, not necessarily that it hurts, or delays healing time. Some studies suggest lowering fever can lead to greater disease transmission2, but findings are inconsistent, and it definitively does mute the body’s self-defense mechanisms. Medications like ibuprofen and acetaminophen can have negative side effects independent of their antipyretic qualities, but they are generally safe at recommended doses. Aspirin can occasionally cause Reye’s syndrome in children with a viral infection, leading to swelling of the brain and liver, so aspirin should be avoided. If body temperature gets above 104o F (40o C), it should be treated. Fever in a newborn is always a concern and should not be ignored.
Fever is also one of the leading causes for pediatric emergency room visits. This is an unnecessary burden on ER facilities, but especially on patients and families who spend an average of 3+ hours at the hospital and can then be stuck with a hefty bill. Fevers rarely require hospital admission and are generally treated with the same medications available at home. Only in rare cases is IV acetaminophen used. Even then, treatment with readily available oral medication is mostly to appease worried parents and to justify an ER visit. Hospital visits for fever correlate with low education and low income, or families that can least afford unnecessary expenses. Part of this is likely due to decreased access to a primary care pediatrician, but this correlation holds true essentially throughout the world, even in countries with universal healthcare (side note: >60% of pediatric ER visits in the US are covered by Medicaid). Both inaccurate and incomplete information contribute to unnecessary visits, and one study in Mexico found that simply owning a home thermometer decreased the rates of hospital visits for fever.
One more point on fever being an unfairly categorized boogeyman: the 1927 Nobel Prize in Medicine was given to Dr. Julius Wagner-Jauregg for treating patients with syphilis by infecting them with malaria. The cyclical high-temperature fevers associated with malaria were enough to somewhat effectively kill the oft-debilitating disease of syphilis, while the patient eventually recovered from malaria. The discovery of penicillin one year later in 1928 quickly put an end to this practice.
Chronic, or long-standing, inflammation is a completely different beast from acute inflammation. Chronic inflammation results from either repeated injury or stimulus constantly inciting an inflammatory response, or the failure of acute inflammation to properly resolve after its job is done. Persistent inflammation is at the root of almost all chronic disease. Unlike acute inflammation, which causes significant discomfort, chronic inflammation is easily ignored. It’s similar to the metaphor of boiling a frog in a pot. If you boil the water right away (acute inflammation), the frog hops out. If you turn the heat up slowly (chronic inflammation), the frog doesn’t notice what’s going on and dies. We often don’t recognize the damage done by chronic inflammation until the damage is significant and often irreversible. We habitually overtreat acute inflammation and severely undertreat acute inflammation.
There are multiple mechanisms by which chronic inflammation is harmful. Part of the inflammatory response is ramping up the activity of various immune cells to fight infection and clear away dead or damaged tissue. Certain immune cells die when the acute period is over while others revert to a less active state. If this doesn’t happen, though, the overly zealous leukocytes can attack healthy cells. This can result in a wide array of symptoms, depending on what cells are being attacked.
Acute inflammation also involves the release of molecular signals that promote healing of damaged tissue. If these signals don’t turn off, it results in an overproduction of collagen and other extracellular matrix components, leading to fibrosis and scarring. Fibrosis can affect organ function as seen in liver cirrhosis or pulmonary fibrosis. Functional cells are essentially being replaced by scar tissue, or the tissue becomes too thick to properly perform its function.
Another usually helpful byproduct of acute inflammation are reactive oxygen species (ROS). They perform signaling roles that increase healing and activate immune cells. Some immune cells even use ROS to directly kill bacteria or viruses. The dark side of ROS is that if there are too many, they can start to cause DNA-level damage to healthy cells. Damage to DNA can then lead to the creation of cancer cells. Chronic inflammation is a strong risk factor for cancer development. It can also cause epigenetic changes, or changes that don’t directly affect the DNA, but does change the expression of many genes.
Persistent inflammation also affects fat metabolism and makes it more likely that cholesterol plaques build up in the arterial walls. This can lead to high blood pressure and increases the risk of heart attack or stroke. It also contributes to insulin resistance. Inflammatory cytokines interfere with insulin signaling pathways, which promotes development of type 2 diabetes and metabolic syndrome.
This isn’t a comprehensive summary, but it shows how many aspects of inflammation can be greatly beneficial, but damaging if not properly regulated. We’ve mentioned COPD, pulmonary fibrosis, type 2 diabetes, hypertension, heart disease, and cancer as being direct results of chronic inflammation, but it is just the tip of the iceberg.
The longer immune cells are overly active during inflammatory states, the more likely autoimmune diseases are to develop. There generally has to be an associated genetic component to develop an autoimmune disease, and some will develop in the absence of chronic inflammation, but it is a strong risk factor for development. Autoimmune diseases include lupus, MS, celiac disease, rheumatoid arthritis, Addison and Graves’ disease, Hashimoto thyroiditis, type 1 diabetes, psoriasis, etc. (The Autoimmune Institute lists 160 different autoimmune diseases3.)
There are also strong links between chronic inflammation and Alzheimer’s disease. Inflammatory signaling molecules in the peripheral circulation easily cross the blood brain barrier (BBB) and can affect the brain. As discussed, fever is a result of cytokines produced elsewhere traveling to the brain and acting on the hypothalamus. Chronic inflammation rarely causes fever, but the persistent inflammatory signals can induce the formation of amyloid-beta plaques (abnormal deposition of protein fragments in the brain) and neurofibrillary tangles (abnormal fibrous growths), both of which are hallmark findings in Alzheimer’s disease. There’s also more and more evidence indicating that chronic inflammation affects mood, including depression, fatigue, and anxiety4.
Chronic inflammation occurs for one of two reasons: Either there’s something in the body causing a persistent response or the response fails to turn off after the stimulus is controlled. Irritants include infections, environmental exposures, and diet. The more times inflammation ramps up, the more likely it is that one of those times it doesn’t turn off correctly, leading to an autoimmune disease.
An autoimmune disease is when an overactive immune system targets one normal cell type and decides to treat it as an invader. For example, in Hashimoto’s thyroiditis, the immune system targets the cells that create thyroid hormone. Once those cells (or a portion of them) are destroyed, the body can’t make enough thyroid hormone. Hashimoto’s is the most common cause of hypothyroidism in the US, but it usually isn’t specifically tested for because confirming the underlying disease process doesn’t change management of the disease. Type 1 diabetes occurs when the immune system destroys pancreatic cells that make insulin. This is different from Type 2 diabetes, which is not an autoimmune disease. Type 2 diabetes results from insulin resistance. The insulin-creating cells in the pancreas must increase production of insulin to lower blood sugar because the liver and other organs are less responsive to insulin. The pancreas eventually may have to make so much insulin that it gets to the point where the cells burn out and stop producing insulin all together.
Again, an autoimmune disease can be strongly genetic and develop no matter what, or someone with a predisposition can be pushed over the edge due to recurrent inflammation. Type 1 diabetes, multiple sclerosis, and lupus have stronger genetic components, so they’re likely to develop regardless of lifestyle. Rheumatoid arthritis, inflammatory bowel disease (including Crohn’s and ulcerative colitis), and psoriasis tend to be more dependent on lifestyle. Either way, once an autoimmune disease develops, it’s essentially impossible to get rid of and the goal is to control the symptoms.
Persistent infections can be a cause of chronic inflammation. Viral infections such as Hepatitis B, C, and HIV, bacterial infections like H. pylori, and parasitic infections can all cause chronic inflammatory responses. Prolonged responses to infections like Lyme disease and COVID are less clearly attributable. These chronic infections generally all have lifestyle components that increase the risk of acquiring them, but some are unavoidable. The viral infections are often acquired through sex or IV drug use (very controllable) but could also be passed from mother to child during birth or through an accidental needle stick in a healthcare worker, or contaminated blood transfusion (very rare, but uncontrollable from the patient’s perspective). H. pylori is more prevalent in areas where living conditions are poor, but it is still often seen in developed countries and occurs seemingly at random. Parasitic infections are also more prevalent in hot, humid climates and when living conditions are poor, and while these are lifestyle-related, most people are limited in their ability to change them.
Extended exposure to environmental irritants can also cause chronic inflammation. Air pollution, heavy metals in contaminated food, water or industrial products, pesticides and herbicides, and other industrial chemicals like those found in plastics and some food packaging can all cause chronic inflammation. Many of these are extremely prevalent in modern day society. Once exposed to one of these irritants, such as heavy metals or microplastics, they can stay in the body indefinitely.
Finally, and most importantly since it is the most controllable factor, diet plays a big role in chronic inflammation. Aside from possible contaminants, the nutrients (to use the term loosely) in food put your body in an inflammatory state. For starters, insulin activates the innate immune response similarly to an invading pathogen5. Insulin is released from the pancreas when blood sugar levels are high. Skeletal muscle, liver, and fat cells are the most responsive to insulin signaling and increase their uptake of blood sugar. Hyperglycemia, or high blood sugar, is in itself irritating and causes an inflammatory response in the blood vessels. Persistent high blood sugar is a double whammy when it comes to inflammation. Not only is the sugar itself inflammatory, but the body’s response of increasing insulin to lower blood sugar creates an additional inflammatory response.
To know which foods will raise blood sugar, and thus are the most pro-inflammatory, it’s important to understand their glycemic index. The glycemic index of various foods is derived by giving test subject 50 grams of the food and then testing their blood sugar two hours later. The higher the spike in blood sugar, the higher the glycemic index. You could run similar experiments on yourself, either by using a glucose monitoring kit and poking your finger two hours after every meal, or by wearing a continuous glucose monitor (CGM) that constantly monitors blood sugar. The foods with high glycemic indices are generally not surprising, and include sugary food and drinks, processed foods (chips and pretzels), fast food, white bread and other refined flour products, etc. Regular consumption of these foods put your body in a state of constant inflammation. Over time, this constant inflammation and constant presence of insulin cause damage to liver and muscle tissue and make it so they’re not as responsive to future insulin signals. This is called insulin resistance and is the first step on the way to type 2 diabetes and metabolic syndrome.
(*Quick side note: Glycemic load is also important. Glycemic index is standardized to a certain amount of food intake, or the potency of the food in raising blood sugar. Glycemic load takes into account the amount of the food you consume. A single nibble of a high glycemic index food with still have a low glycemic load, and thus a lower rise in blood sugar, because the portion is so small. A giant plateful of a relatively lower glycemic index food will have a high glycemic load and raise blood sugar. Glycemic load is more related to the concomitant rise in blood sugar than glycemic index.)
Since blood sugar is the body’s main source of energy, persistently high blood sugar and persistently high insulin levels lead to increased energy storage, which means increased fat. Fat cells themselves are inherently pro-inflammatory. Obesity is a state of chronic inflammation. You can easily see that chronic inflammation is an ever-increasing feedback loop of inflammation. Unhealthy foods cause inflammation through multiple routes, and result in increased fat, which itself causes inflammation, which leads to further damage to organs and increased inflammation and obesity.
Other “nutrients” that can be pro-inflammatory independent of carbohydrate (sugar) content include omega-6 polyunsaturated fats found in corn, safflower, soybean, and sunflower oils. Saturated fats found in red meat and dairy have also been shown to induce inflammation, although it is through a different pathway than commonly associated with other inflammatory stimuli. It also seems to be related to how immune cells interact with existing fat cells, so saturated fat is likely more inflammatory to those who already have an abundance of fat cells, and less so to those who are lean. It is also odd that out of the most pro-inflammatory foods, they are all highly processed, synthetic derivatives of whole foods, except for saturated fats, which occur naturally in many foods that have been a stable in human diets for millennia. There is also significant evidence6 to show a concerted effort to demonize red meat by industries that produce all the other pro-inflammatory foods we’ve discussed in an attempt to cast blame on meat rather than their own products. These vilification efforts have recently been adopted by animal rights and climate activists. It seems apparent that when talking about pro-inflammatory foods, while there are studies that show inflammatory qualities of saturated fat, it is clearly an outlier compared to the other foods in this category and conclusions about its damaging effects should be taken with a grain of salt. (Salt, ironically, is also often unfairly criticized for the negative effects primarily caused by sugar.)
We know very well that chronic inflammation is severely damaging to health and can lead to a range of terrible diseases, including cancer. The problem is it acts very slowly; so slowly that we often don’t feel the need to address it with urgency. We also know very well what causes chronic inflammation. Some of these causes are apparent and avoidable. Some are unavoidable, or far less easily avoidable. Many are ingrained into society and literally would take an act of Congress to prevent future exposure (ie use of pesticides, dangerous food additives, and damaging microplastics). Unfortunately, and for various reasons, America is behind much of the developed world when it comes to banning these chemicals. But even when it comes to avoidable inflammatory triggers, we still respond poorly.
It should be clear that a major source of inflammation in the body is due to diet. Many dietary guidelines are contradictory and confusing. Even foods that should be relatively healthy have so many hidden additives that they are more problematic than they should be. Signs and symptoms of chronic inflammation, i.e. an expanding waistline, skin rashes, gut discomfort, etc., are either ignored or treated with a medication to suppress the symptoms rather than treat the underlying cause (see our article here).
To paraphrase Homer Simpson, “Inflammation is the cause of, and solution to, all of life’s problems.” It is truly a double-edged sword. Acute inflammation is necessary for proper healing and recovery. Chronic inflammation is extremely damaging to our health. Paradoxically, we overtreat acute inflammation and undertreat chronic inflammation. It’s time to hop out of water pot before it boils and address controllable causes of chronic inflammation before it’s too late.
References
1. http://drmirkin.com/fitness/why-ice-delays-recovery.html
2. “Population Effects of Lowering Fever” Earn, et. al.
3. https://www.autoimmuneinstitute.org/resources/autoimmune-disease-list/
4. “The Role of Inflammation in Depression and Fatigue”; Lee and Giuliani
5. “Regulation of the Immune System by the Insulin Receptor in Health and Disease”; Makhijani, et. al.
6. “The Big Fat Lie” by Nina Teicholz (it takes a whole book to outline the deceptive practices of the big food industry)