Sunday, March 10, 2013

Causes of Inflammation

This isn’t a complete list, but includes several possible causes of chronic inflammation.  Unlike the other posts I changed the reference count to reset at each sub-heading to make this post easier to edit

Autoimmune Diseases, Allergies and Asthma

With autoimmune diseases the immune system attacks the body’s tissues, causing inflammation not only locally, but often systemically as well.  So it’s not surprising then, that inflammatory markers are elevated in people who have autoimmune diseases [1].  People who have an autoimmune disease will likely have a poorly regulated immune system and intestinal permeability, both of which can be inflammatory regardless of autoimmunity and a factor in other diseases as well.  People who have allergies and asthma have an inappropriate immune response to certain stimuli suggesting that they also have a poorly regulated immune system and that the diseases may be a source of chronic inflammation.  See Autoimmune Disease

Chronic Stress / Glucocorticoid Resistance

Glucocorticoids (such as cortisol) have anti-inflammatory effects by suppressing the immune system.  Glucocorticoid resistance (GCR) is where glucocorticoids fail to adequately suppress the HPA axis and the immune system when needed, which results in elevated glucocorticoid levels and a more intense and prolonged inflammatory response.  Glucocorticoid resistance can be caused by inflammatory cytokines and chronic stress [1] [2] [3] and is thought to affect “between 40 and 60% of depressed patients, especially those presenting melancholic and/or psychotic symptoms” [1].

Homocysteine

Homocysteine (Hcy) is formed when methionine donates a methyl group (CH3) (often to DNA in a process called DNA methylation, which regulates whether genes are turned on or off).  Inflammation increases homocysteine [1], and homocysteine increase oxidative stress [2] and ER stress [3], but it can be converted to other molecules through several means: (1) vitamin B6 is a cofactor of an enzymatic reaction that converts homocysteine to cysteine; (2) a metabolite of folate and a vitamin B12 related enzyme can recycle homocysteine back to methionine; and (3) a metabolite of choline (betaine) can donate a methyl group to homocysteine, which converts it back to methionine.  While vitamin B6, B12 and folate shouldn’t be an issue for someone eating a whole food, omnivorous diet it’s unlikely that one would get sufficient choline without regularly consuming eggs, organ meat or a fair bit of either muscle meat of whole wheat.  See my nutrient database.  Also, Chris Masterjohn discusses the importance of glycine to promote glutathione synthesis and avoid excessive methylation.  See Beyond Good and Evil: Synergy and Context With Dietary Nutrients

Insulin Resistance

Insulin resistance (IR) leads to elevated free fatty acids and hyperglycemia, which increases oxidative stress and inflammation.  Insulin resistance can also promote inflammation by reducing insulin signalling in some places and increasing it in others.  For example, insulin increases endothelial nitric oxide synthase (eNOS) and insulin resistance results in lower eNOS [2]; and insulin increases the activity of the RAAS and insulin resistance results in higher RAAS activity from this direct effect [3] but also from elevated FFA activating the sympathetic nervous system and then the RAAS [4].  See What Causes Insulin Resistance? Part VII (and the previous 6 posts), Mitochondrial Dysfunction and Overweight but Insulin Sensitive and Normal Weight but Insulin Resistant: Part 1 (and Part 3)

Iron Overload

While iron is essential to life and is needed for many important functions, too much iron can be a problem.  Free iron is toxic to cells as hydrogen peroxide (H2O2) can react with iron ions to produce highly reactive hydroxyl radicals (OH-), which is known as the Fenton reaction.  To prevent this from happening we have a protein called ferritin that stores iron.  Blood ferritin levels increase when the body's iron stores increase.  But ferritin is also an acute phase reactant, and increases in response to infections and inflammation because ferritin makes iron unavailable for pathogens, which require iron for growth and proliferation (so high ferritin may not necessarily mean high iron).  Phlebotomy can lower markers of the metabolic syndrome [1].  See Chris Kresser’s AHS 2012 talk for information on the causes, problems, testing and treatment of iron overload

Lipopolysaccharide/Endotoxins

Lipopolysaccharide (LPS) is an endotoxin of gram-negative bacteria that activates the immune system and triggers a strong inflammatory response.  LPS is often used experimentally to cause inflammation and certain diseases in animal models [1] [2].  Other bacterial products and DNA also promote strong inflammatory response.  See Leptin Resistance for now on some causes of elevated LPS from the (I plan to do a series on gut health at some point), but remember that LPS can also come from bacteria in the mouth, and see Is Postprandial LPS From Fats a Cause for Concern?

Mitochondrial Dysfunction

Mitochondria generate most of the ATP our cells use from the macronutrients in food, but also roughly 90% of all endogenous reactive oxygen species (ROS).  ROS are physiological signalling molecules, but in excess they can overwhelm antioxidant defences, leading to oxidative stress and inflammation [1] [2].  See Mitochondrial Dysfunction

Obesity

While obesity can be caused by inflammation, inflammation can also be a consequence of obesity through a few different mechanisms: (1) as the adipocytes fill up they become progressively more insulin resistant, leading to elevated FFA which binds to TLR4 on macrophages and initiates an inflammatory response, causing an increase in pro-inflammatory cytokines, macrophage infiltration in adipocytes, etc [1]; (4) as the abdominal adipocytes (in particular) fill up they may also become hypoxic, which triggers the release of an inflammatory molecule called HIF-1α [2]; and (2) obesity results increases the activity of the RAAS due to increased sympathetic activity from leptin [3] and greater release of angiotensinogen (ACE converts it to angiotensin) from adipocytes [4].  However, some overweight/obese people are insulin sensitive and don’t have chronic inflammation.  See Obesity

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