All about inflammation and anti-inflammatory lifestyle (Part 1)

inflammation

Over the course of evolution, our bodies developed some fantastically complex and truly amazing defense mechanisms.  Jointly, they keep us safe and alive, protecting us from foreign bacterial and viral invasions, ensuring tissue regeneration and healing, cleaning up cellular metabolic debris and deactivating and destroying malfunctioning cells to limit the damage that they can inflict on surrounding tissues.

Many times, however, the same processes that are supposed to protect our bodies from harm cause greater harm when allowed to progress unchecked.  For instance, cholesterol patches originally deployed to limit the damage from vascular lesions may lead to dangerous plaque formations that elevate the risk of cardiovascular disease and stroke.  Free radicals, the generation of which is a part of normal ATP production in mitochondria wreak havoc in large amounts – to a point of causing DNA damage. Our immune system, designed to combat foreign microbes and irritants and keep us safe, can go out of control and cause a whole range of dysfunctions – from benign allergies to serious auto-immune disorders like lupus or arthritis, when it loses the ability to differentiate between foreign invaders and host tissues.

This article will discuss yet another biological process that is a part of your innate immune system and is intended to protect you from harm, but often gets out of control and creates the opposite effect.

We are, of course, talking about inflammation.

You probably hear about it quite often – most likely in the negative context.  From doctors prescribing anti-inflammatory drugs, many popular websites talking about anti-inflammatory foods and diets, etc. – but just as in many other cases, most of these measures are trying to fight the symptom, rather than the root cause.

What exactly is inflammation and should you really fear it or fight it?  What causes it and what effects does it have on your body?  What should you do to control it and how can you minimize any negative effects?

Continue reading to find out!

What is inflammation?

In a broad sense, inflammation is a protective response to cell injury (physical, thermal, chemical, viral, etc.) involving immune cells, blood vessels and molecular mediators.  Visually, it most often manifests itself as a localized physical in which a part of the body becomes reddened, swollen, warm and sensitive to touch.

The function of the inflammatory response is to eliminate the initial cause of cell injury, clear out damaged necrotic cells and tissues and to initiate tissue repair.  This initial response is called acute inflammation and involves a series of biochemical events.

Acute inflammation is characterized by increased vasodilation (hence the redness) and permeability of blood vessels surrounding the injured tissue, which results in leakage of plasma, leukocytes and fluid containing anti-microbial mediators into that damaged tissue (hence the swelling) and overall increased local blood flow (hence the rise in surrounding tissue temperature).  At the same time, some of the released molecular mediators increase the sensitivity to pain.   This response ensures both immediate damage to microbes and their marking (opsonisation) for subsequent destruction by phagocytes.  Some of the exuded tissue fluid is also funnelled to the regional lymph nodes, flushing bacteria along to start the recognition and attack phase of the adaptive immune system.

Resolution of inflammation

Inflammation is destructive to the tissue in which it takes place – the molecular mediators and effectors involved in the inflammatory response are extremely powerful and do not discriminate among microbial and host targets.  Therefore, acute inflammation is typically resolved and actively terminated within a few days, once its purpose (destruction of invading pathogens and facilitation of tissue repair) is achieved.

Resolution occurs by different mechanisms in different tissues, including production of anti-inflammatory specialized pro-resolving mediators, downregulation of pro-inflammatory molecules, upregulation of anti-inflammatory molecules, apoptosis of pro-inflammatory cells, desensitization of receptors, etc.

In fact, evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues, granulocytes (a type of white blood cell and a major part of innate immune system) initiate the termination sequence – neutrophil recruitment ceases and programmed death by apoptosis is triggered. These events coincide with the biosynthesis of special molecules (resolvins and protectins), from Omega-3 fatty acids, which initiate apoptosis, clear out neutrophils and generally exhibit potent anti-inflammatory properties.  The anti-inflammatory program ends with the departure of macrophages through the lymphatic system.

At the end of such active resolution, vasodilation, chemical production, and leukocyte infiltration cease, and cells regenerate. In situations where limited or short-lived inflammation has occurred this is usually the outcome.

What if inflammation is fully eliminated – and can there be too much of it?

Everybody knows inflammation is bad and tries to fight it – but if you were to fully suppress it (say, by taking a large dose of anti-inflammatory drugs), it would actually do your body a great disservice.  In fact, it could lead to progressive tissue destruction by the harmful stimulus (e.g. bacteria) and compromise the survival of the organism. Your body would lose its natural ability to fight off invaders and would, eventually, fully succumb to the infection and stop functioning.

Yet, as beneficial as inflammatory response may be for saving your life, it has quite a few downsides when allowed to progress.  Normal inflammation is self-limiting, because the production of anti-inflammatory cytokines follows the pro-inflammatory cytokines closely.  However, persistence of the initiating factors or failure of mechanisms required to resolve the inflammatory response leads to chronic inflammation (more on this below).

Recent research shows that inflammation is a major factor in the progression of various chronic diseases/disorders – both local and systemic.  Here are just a few common examples of disorders associated with inflammation: acne, autoimmune diseases, arthritis, asthma, atherosclerosis, celiac disease, colitis, allergies and hypersensitivities, inflammatory bowel syndrome, otitis, rheumatic fever, rhinitis, vasculitis, cancer, etc. – the list can go on and on.

There may also be a link between mental health and inflammation. Studies show that people experiencing higher levels of stress and depression display elevated C-reactive protein and IL-6 levels (both markers of inflammation), but it is not fully understood whether inflammation causes mental health issues or mental health issues cause inflammation.  Still, a very strong association is definitely there.

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Association with cancer

Inflammation is now widely accepted to be a critical component of tumor progression. Many cancers arise from sites of infection, chronic irritation and inflammation, as inflammatory cells create an environment that fosters proliferation, survival and migration.  In fact, epidemiological studies estimate that nearly 15 percent of the worldwide cancer incidence is associated with microbial infection.

Obviously, not all inflammation results in tumors.  In fact, your body’s own immune system is very good at catching and eliminating malignant cells most of the time, through various tumor suppressor pathways that mediate DNA repair, cell cycle arrest, apoptosis and senescence.  But persistent inflammatory environment often contributes to the increased risk of cancer by influencing initiation and proliferation of mutated cells, and suppression of tumor-detection pathways.  In the face of massive cell death occurring in infection or non-infectious tissue injury, lost cells must be repopulated by the expansion of other cells, often undifferentiated precursor cells such as tissue stem cells.  In an extension of its physiologic role in mediating tissue repair or as a strategy in host defense to infection, the inflammatory response may play a role in providing survival and proliferative signals to initiated cells, thereby leading to tumor promotion.

Initial DNA alterations are induced by viral or chemical carcinogens – this stage is known as “initiation”.  During the initiation stage, leukocytes and other phagocytic cells induce DNA damage in proliferating cells, through their generation of reactive oxygen and nitrogen species (reactive oxygen intermediaries, hydroxyl radical, superoxide, reactive nitrogen intermediates, nitric oxide and peroxynitrite).  These reactive species are produced normally by those cells to fight infection, but repeated tissue damage and regeneration in the presence of highly reactive nitrogen and oxygen species released from inflammatory cells often results in permanent alterations to the genome – such as point mutations, deletions, or rearrangements. As such, cells that sustain DNA damage continue to proliferate in microenvironments rich in inflammatory cells and growth/survival factors that support their growth.

This state, however, is usually reversible and normally mitigated by apoptosis (programmed cell death) or senescence (a “dormant” state in which the cell stops reproducing).  Cell proliferation is enhanced while the tissue regenerates and normally subsides after the assaulting agent is removed or the repair completed.  In fact, cells require the second type of stimulation (referred to as “promotion”) to develop into a cancer. Promotion can result from exposure of initiated cells to chemical irritants, factors released at the site of wounding, hormones or – our primary subject – chronic irritation and inflammation. Many promoters, whether directly or indirectly, induce cell proliferation, recruit inflammatory cells, increase production of reactive oxygen species leading to oxidative DNA damage, and reduce DNA repair.  For instance, inflammation stimulates a rise in levels of a molecule called microRNA-155 (miR-155), which, in turn, causes a drop in levels of proteins involved in DNA repair, resulting in a higher rate of spontaneous gene mutations.

Cumulatively, all of this creates conditions that are very favorable for cancer growth.  In other words, while brief inflammatory response is probably not enough to cause much damage, prolonged chronic inflammation may lead to sustained proliferation of DNA-damaged cells in an environment rich in inflammatory cells, growth factors and agents promoting further damage, thus increasing cancer risk.

Increased cell damage, large number of mutagens and resulting cell death during prolonged inflammatory response may be enough of a cause to warrant the survival of some initiated cells and their expansion as a compensatory mechanism.  In fact, repeated exposure of lab mice to mutagens alone has been shown to induce tumorigenesis.

The inflammatory response may also have a role in other aspects of cancer progression, such as tissue invasion and metastasis (which is the cause of 90% cancer mortality).

The strongest association of chronic inflammation with malignant diseases is in colon carcinogenesis arising in individuals with inflammatory bowel diseases, for example, chronic ulcerative colitis and Crohn’s disease. Similarly, Hepatitis C infection in the liver predisposes to liver carcinoma, schistosomiasis predisposes to bladder and colon carcinoma and chronic Helicobacter pylori infection is the world’s leading cause of stomach cancer and the second most common type of cancer globally.

Several tissues changes occur as cancers grow – activation of the HIF1 pathway and subsequent angiogenesis (formation of new blood vessels that play a big role in migration and metastasis of tumor cells), degradation of epithelial barriers, disruption of the extracellular matrix, etc. All of these processes are likely to stimulate homeostatic processes of tissue repair, including the recruitment of inflammatory leukocytes. These responses lead to tumor growth itself, thus promoting a positive feedback loop.

Effect on cognition and mood disorders

It has been long suspected that inflammation might play a role in the rapid, short-term lowering of cognition. And although it’s inherently difficult to isolate the precise factors that affect cognition amid the storm of molecular changes that occur during inflammation, several studies seem to have been making progress.

For instance, animal studies suggest that exposure to a respiratory virus lead to activation of immune cells in the hippocampus—an important memory-related brain region and the expression of inflammatory genes across the brain.  The infected animals performed significantly worse on spatial memory tests – even three weeks after their infections began.

Other animal studies have confirmed that exposure to bacterial protein that induces neuroinflammation and, thus, causes a surge in pro-inflammatory factor TNF-α also triggers hippocampus-related cognitive deficits. Interestingly, those cognitive deficits were reversed after a compound that inhibits TNF-α production was used.

The feedback loop, in which inflammation may cause cancer which, in turn, may cause more inflammation means the two conditions are complimentary.  Not only inflammation may cause cancer, but cancer may cause inflammation as well.  Impaired mood and cognition often manifest themselves in cancer patients even before they are diagnosed – some studies on animals confirm elevated levels of inflammation markers in their hippocampi with the resulting increase in depression-like behavior and impaired object recognition.

Inflammation is also known to disrupt mood and cause depression – even in patients with no previous history of mental disorders – to the extent of inflammation being suspected as the cause of depression-related suicides.

Chronic or systemic inflammation

And now – the most important part.  Despite all the potential effects, isolated acute inflammatory response that resolves itself quickly is unlikely to cause major problems.  However, things change dramatically when this response never truly subsides – turning into chronic (also called “systemic” inflammation).

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Although inflammation in general is a vital response of human immune system, the state of chronic inflammation can have several secondary consequences associated with enhanced risk of chronic diseases and disorders. Chronic inflammation in tissue usually happens when inflammatory responses arise in the absence of actual stimulus. It usually takes place due to infections that are not resolved, persistence of foreign bodies, continuous chemical exposures, recurrent acute inflammation, or specific pathogens.

An infectious organism, if it is not contained by the actions of acute inflammation, can escape the immediate tissue via the circulatory system or lymphatic system, where it may spread to other parts of the body. When lymph nodes cannot destroy all pathogens, the infection spreads further. A pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system.

Inflammation then may overwhelm the host, leading to systemic inflammatory response, called sepsis – vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death.

But systemic inflammation is not always as extreme.  Sometimes, when injurious agents persist, it takes the form of a low-grade chronic inflammation that is “neither here nor there” – in other words, there is no immediate sweeping response to trauma and no immediate and quick tissue destruction, but such low-grade inflammation keeps the body in a constant state of repair response.  Immune cells (macrophages, monocytes, and lymphocytes) take charge, and a recurring, process of tissue destruction and repair effort develops and continues until the source of the chronic inflammation is removed.  This process, marked by inflammation lasting many days, months or even years – and may never truly stop, leading to the formation of a “chronic wound” – one that is not always apparent.

Chronic inflammation is characterised by the dominating presence of macrophages in the injured tissue. These cells are powerful defensive agents of the body, but the toxins they release (including reactive oxygen species) are injurious not only to the invading bodies, but also to the organism’s own tissues. As a consequence, chronic inflammation is almost always accompanied by tissue destruction.

The danger of low-grade systemic inflammation

The concept of systemic inflammation developed with the discovery of interleukins (IL) – a group of naturally occurring proteins that mediate communication between cells and regulate cell growth, differentiation and motility.

Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular site, organ or tissue but involves the endothelium and other organ systems.  Without lab tests for specific markers of inflammation, there may be a lack of easily identifiable symptoms (pain, redness, swelling) that we rely on to identify acute inflammation.

But lack of symptoms doesn’t always mean lack of problems.  As you have already learned, neutrophils, one of the cells involved in inflammatory response, attack what they perceive as outside damage/invaders with the massive production of free radicals. They and other cells will keep pumping and spreading these free radicals throughout the body as long as they sense the inflammation. Free radicals also destroy healthy cell walls and DNA, so there is collateral damage. In addition, the body’s general immune response (the ability to deal with daily exposure to bacteria, virus and fungus) is compromised because the system is kept busy tending to the incessant, active inflammation.

Long-term effects of chronic inflammation can influence the development of many conditions discussed above, such as Chrohn’s disease, hay fever, periodontitis, rheumatoid arthritis, cancer, etc. Countless studies have connected chronic inflammation with the development of atherosclerosis.  In the article on cholesterol, we discussed how plaques get formed when your body applies cholesterol “patches” to inflamed endothelium of your blood vessels to prevent further damage, creating arterial blockage as a result – chronic systemic inflammation is actually what drives this.

Inflammation exists in patients with infections, environmental diseases (asbestos exposure and smoke inhalation, etc.), immune diseases, and chronic diseases like diabetes and other metabolic disorders, gout, rheumatoid arthritis, osteoarthritis, cancer, and others. It has also been evident that a variety of illnesses have shown inflammatory response such as venous and chronic arterial diseases, myocardial ischemia, Alzheimer’s disease, acute cerebral stroke, cancer, and arterial hypertension.

Dietary and lifestyle habits can cause chronic inflammation

It’s not necessarily just viral or bacterial assault that can cause chronic low-grade inflammation – ongoing health issues such as diabetes, high blood pressure and autoimmune disorders can instigate the same.  In many cases, those health issues themselves are caused by poor dietary habits and poor lifestyle choices.

For instance, chronic inflammation is widely observed in obesity.  The obese commonly have many elevated markers of inflammation, including IL-6 (Interleukin-6), IL-8 (Interleukin-8), IL-18 (Interleukin-18), TNF-α (Tumor necrosis factor-alpha), CRP (C-reactive protein) alongside with insulin, blood glucose and leptin.  This, by the way, is a great example of how you can impair cognitive abilities (among other things) by poor dietary choices – research shows that even relatively short exposures to high-sugar or high-fat and high sugar diets impair the function of the brain’s hippocampus and lead to worse memory test results – even before any weight differences start to emerge.

Low-grade chronic inflammation is characterized by a two- to threefold increase in the systemic concentrations of cytokines such as TNF-α, IL-6, and CRP.  Waist circumference correlates significantly with systemic inflammatory response – and obesity overall triggers inflammation through a large variety of different mechanisms.  On the other hand, loss of white adipose tissue reduces levels of inflammation markers.

Elevated levels of C-reactive protein (CRP) – a key marker of inflammation – are observed in obese individuals. Elevated CRP is also associated with heart attacks, strokes, high blood pressure and muscle weakness.

What does this all mean?

The verdict is clear – excessive inflammation – especially the one that lasts longer than just a few days and often progresses without you knowing – is not normal.  In fact, it is dangerous and can kill you, triggering a wide variety of medical conditions.  So you have to do what you can to lower the risk of low-grade systemic inflammation and remove the factors that trigger it.

We will focus on the relevant strategies to reduce and eliminate inflammation in Part II.