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Inflammation (Chronic)

Of the ten leading causes of mortality in the United States, chronic, low-level inflammation contributes to the pathogenesis of at least seven. These include heart disease, cancer, chronic lower respiratory disease, stroke, Alzheimer’s disease, diabetes, and nephritis (Centers for Disease Control and Prevention 2011; Bastard et al. 2006; Cao 2011, Jha et al. 2009; Ferrucci et al. 2010; Glorieux et al. 2009; Kundu et al. 2008; Murphy 2012; Singh et al. 2011).

Inflammation has classically been viewed as an acute (short term) response to tissue injury that produces characteristic symptoms and usually resolves spontaneously. More contemporary revelations show chronic inflammation to be a major factor in the development of degenerative disease and loss of youthful functions.

Chronic inflammation can be triggered by cellular stress and dysfunction, such as that caused by excessive calorie consumption, elevated blood sugar levels, and oxidative stress. It is now clear that the destructive capacity of chronic inflammation is unprecedented among physiologic processes (Karin et al. 2006).

The danger of chronic, low-level inflammation is that its silent nature belies its destructive power.

In fact, stress-induced inflammation, once triggered, can persist undetected for years, or even decades, propagating cell death throughout the body. Due to the fact that it contributes so greatly to deterioration associated with the aging process, this silent state of chronic inflammation has been coined “inflammaging”.

Chronic low-level inflammation may be threatening your health at this very moment, without you realizing it. In this protocol you will learn about low-cost blood tests that can assess the inflammatory state within your body. You’ll also discover novel approaches that combat chronic inflammation to help avoid age-related health decline.

The Inflammatory Process

The Acute Inflammatory Response

Inflammation, the adaptive immune response to tissue injury or infection, plays a central role in metabolism in a variety of organisms (Medzhitov 2008).

At its most basic level, an acute inflammatory response is triggered by 1) tissue injury (trauma, exposure to heat or chemicals); or 2) infection by viruses, bacteria, parasites, or fungi. The classic manifestation of acute inflammation is characterized by four cardinal signs: Redness and heat result from the increased blood flow to the site of injury. Swelling results from the accumulation of fluid at the injury site, a consequence of the increased blood flow. Finally, swelling can compress nerve endings near the injury, causing the characteristic pain associated with inflammation. Pain is also important to make the organism aware of the tissue damage. Additionally, inflammation in a joint usually results in a fifth sign (impairment of function), which has the effect of limiting movement and forcing rest of the injured joint to aid in healing.

A well-controlled acute inflammatory response has several protective roles:

  • It prevents the spread of infectious agents and damage to nearby tissues;
  • helps to remove damaged tissue and pathogens, and;
  • assists the body’s repair processes

However, a third type of stimuli, cellular stress and malfunction, triggers chronic inflammation, which, rather than benefiting health, contributes to disease and age-related deterioration via numerous mechanisms.

Cellular Stress & Chronic, Low-Level Inflammation

Mitochondria – cellular organelles responsible for generating biochemical energy in the form of adenosine triphosphate (ATP) – are a fundamentally necessary component of life in higher organisms. In fact, in the case of sophisticated multicellular life forms, organismal viability depends upon optimal mitochondrial function. Paradoxically, mitochondrial processes can also bring about a tissue-destroying inflammatory mediator known as the inflammasome; this phenomenon is provoked by damaged and dysfunctional mitochondria (Green 2011).

Mitochondrial dysfunction arises consequent of exposure to exogenous (e.g. environmental toxins, tobacco smoke) and endogenous (e.g. reactive oxygen species) stressors, and as a result of the aging process itself. For example, a byproduct of mitochondrial energy generation is the creation of free radical molecules. Free radicals can damage cellular structures and initiate a cascade of proinflammatory genetic signals that ultimately results in cell death (apoptosis), or worse, uncontrolled cell growth - the hallmark of cancer.

Aging is associated with declining mitochondrial efficiency and increased production of free radical molecules. Recent research identifies this age-associated aberration of mitochondrial function as a principle actuator of chronic inflammation (Dinarello 2011). Specifically, mitochondrial dysfunction brings about inflammation as follows:

  1. Accumulation of free radicals induces mitochondrial membrane permeability;
  2. Molecular components normally contained within the mitochondria leak into the cytoplasm (intracellular fluid in which cellular organelles are suspended);
  3. Cytoplasmic pattern recognition receptors (PRR’s), which detect and initiate an immune response against intracellular pathogens, recognize the leaked mitochondrial molecules as potential threats;
  4. Upon detection of the potential threat, PRR’s form a complex called the inflammasome that activates the inflammatory cytokine interleukin-1β, which then recruits components of the immune system to destroy the “infected” cell (Tschopp 2011).

These four steps represent a simplified scheme of mitochondrial dysfunction leading to cellular destruction; however, intracellular free radicals are not the only inducers of inflammatory cell death.

Circulating sugars, primarily glucose and fructose, are culprits as well. When these “blood sugars” come in contact with proteins and lipids a damaging reaction occurs forming compounds called advanced glycation end products (AGEs). AGEs bind to the cell-surface receptor called receptor for advanced glycation end products, or RAGE. Upon activation, RAGE triggers the movement of the inflammatory mediator nuclear factor kappa-B (NF-kB) to the nucleus, where it activates numerous inflammatory genes (Mosquera 2010). Advanced glycation end products are primarily formed in vivo, and glycation is exacerbated by elevated blood sugar levels. However, dietary AGEs also contribute to inflammation; they are abundant in foods cooked at high temperatures, especially red meat (Witko-Sarsat et al. 1998; Vlassara et al. 2002).

Additional biochemical inducers of a chronic inflammatory response include:

  • Uric acid (urate) crystals, which can be deposited in joints during gouty arthritis; elevated levels are a risk factor for kidney disease, hypertension, and metabolic syndrome (Martinon et al. 2006, Alvarez-Lario et al. 2011);
  • Oxidized lipoproteins (such as LDL), a significant contributor to atherosclerotic plaques (Nguyen Khoa et al. 1999); and
  • Homocysteine, a non-protein-forming amino acid that is a marker and risk factor for cardiovascular disease, and may increase bone fracture risk (Au-Yeung et al. 2006).

Together, these proinflammatory instigators promote a perpetual low-level chronic inflammatory state called para-inflammation (Medzhitov 2008).

Although it progresses silently, para-inflammation presents a major threat to the health and longevity of all aging humans. Chronic, low-level inflammation is associated with common diseases including cancer, type II diabetes, osteoporosis, cardiovascular diseases, and others. Thus, by targeting the myriad physiological variables that can inaugurate an inflammatory response, one can effectively temper chronic inflammation and reduce their risk for inflammatory diseases.

Markers and Mediators of Inflammation

Following is a list of some of the most prominent markers of inflammation used in research and diagnosis. Some can be detected by blood tests (see “Diagnosis and Conventional Treatment of Chronic Inflammation”, below):

Tumor necrosis factor alpha (TNF-α) is an intercellular signaling protein called a cytokine, which can be released by multiple types of immune cells in response to cellular damage, stress, or infection. Originally identified as an anti-tumor compound produced by macrophages (immune cells) (Green et al. 1976), TNF-α is required for proper immune surveillance and function. Acting alone or with other inflammatory mediators, TNF-α slows the growth of many pathogens. It activates the bactericidal effects of neutrophils, and is required for the replication of several other immune cell types (Sethi et al. 2008). Excessive TNF-α, however, can lead to a chronic inflammatory state, can increase thrombosis (blood clotting) and decrease cardiac contractility, and may be implicated in tumor initiation and promotion (Kundu et al. 2008).

Nuclear factor kappa-B (NF-kB) is important in the initiation of the inflammatory response. When cells are exposed to damage signals (such as TNF-α or oxidative stress), they activate NF-kB, which turns on the expression of over 400 genes involved in the inflammatory response (Sethi et al. 2008). These include other inflammatory cytokines, and pro-inflammatory enzymes including cyclooxygenase-2 (COX-2) and lipoxygenase. COX-2 is the enzyme responsible for synthesizing pro-inflammatory prostaglandins, and is the target of non-steroidal anti-inflammatory drugs (ibuprofen, aspirin) and COX-2 inhibitors (Celebrex®).

Interleukins are cytokines that have many functions in the promotion and resolution of inflammation. Pro-inflammatory interleukins that have been the subject of most research include IL-1β, IL-6, and IL-8. IL-1β helps immune cells to move out of blood vessels and into damaged or dysfunctional tissues. IL-6 has both pro-inflammatory and anti-inflammatory roles, and coordinates the production of compounds required during the progression and resolution of acute inflammation. IL-8 is expressed by both immune and non-immune cells, and helps to attract neutrophils (immune cells that can destroy pathogens) to sites of injury.

C-reactive protein (CRP) is an acute-phase protein, one of several proteins rapidly produced by the liver during an inflammatory response. Its primary goal in acute inflammation is to coat damaged cells to make them easier to recognize by other immune cells (Meyer 2010). CRP elevation above basal levels is not diagnostic on its own, as it can raise in several cancers, rheumatologic, gastrointestinal, and cardiovascular conditions, and infections (Windgassen et al. 2011). Elevation of CRP (as determined by a high-sensitivity CRP assay or hs-CRP) has a strong association with elevated risk of cardiovascular disease and stroke (Emerging Risk Factors Collaboration et al. 2010).

Eicosanoids. The cytokine factors mentioned above (interleukins, TNF-α) are “long-distance messages”. They are produced by cells at the site of inflammation and released into the blood, carrying information about the inflammatory response throughout the body. In contrast, eicosanoids are “local” messages; they are produced by cells that are proximal to the site of inflammation, and are meant to travel short distances (locally within the same organ, to neighboring cells, or sometimes only to different parts of the same cell) in order to elicit immune defenses (Luo et al. 2011). There are several families of eicosanoids (including prostaglandins, prostacyclins, leukotrienes, and thromboxanes) that are created by most cell types in all major organ systems. Aside from their roles in inflammation (and anti-inflammation), prostaglandins have a variety of functions in cell growth, kidney function, digestion, and the constriction and dilation of blood vessels. Thromboxanes are important mediators of the blood clotting process. Pro-inflammatory leukotrienes are important for recruiting and activating white blood cells during inflammation, and are best studied for their role in airway constriction and anaphylaxis.

Cells produce eicosanoids using unsaturated fatty acids that are part of their cell membranes. The fatty acid starting materials for eicosanoid synthesis are the essential fatty acids linoleic acid (omega-6) and its derivative arachidonic acid (AA); and alpha-linolenic acid (an omega-3) and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). While generalizations about roles of these fatty acids in eicosanoid synthesis should be approached cautiously, the most potent inflammatory eicosanoids are produced from omega-6 fatty acids (linoleic and arachidonic acids). Diets high in omega-3 fatty acids are associated with lower biomarkers of inflammation and cardiovascular disease risk; proposed mechanisms include the production of less inflammatory or anti-inflammatory eicosanoids and through the cyclooxygenase and lipoxygenase enzymes (see below) (Serhan et al. 2001).

Cyclooxygenases and Lipoxygenases. The eicosanoids (above) require several enzymatic steps to be synthesized from unsaturated fatty acids; the cyclooxygenase (COX) and lipoxygenase (LOX) enzymes catalyze the first steps in these reactions. Cyclooxygenases initiate the conversion of omega-3 and omega-6 derivatives into one of the many prostaglandins or thromboxanes. The interest in COX enzyme metabolism comes from the fact that its inhibition leads to decreased prostaglandin synthesis, and therefore a reduction in inflammation, fever, and pain. The analgesic and anti-inflammatory activity of aspirin and the non-steroidal anti- inflammatory drugs (NSAIDS, like ibuprofen and naproxen) is due to their inhibition of COX enzymes. There are two COX enzymes with well-defined roles in humans (COX-1 and COX-2). COX-2 has the most relevance to the inflammatory process: it is normally inactive, but is turned on during inflammation and stimulates this process of inflammation by creating pro-inflammatory prostaglandins and thromboxanes.

Lipoxygenases convert fatty acids into proinflammatory leukotrienes, important local mediators of inflammation. Several potent inflammatory leukotrienes are produced by 5-LOX in mammals. Lipoxygenase enzymes, and the pro-inflammatory factors they produce, have a fundamental role in the inflammatory process by aiding in the recruitment of white blood cells to the site of inflammation. They also stimulate local cells to produce cytokines, which amplifies the inflammatory response (Luo et al. 2011). Thus, LOX enzymes may be involved in a wide variety of inflammatory conditions, and represent an additional target for anti-inflammatory therapy

While COX and LOX enzymes are most often associated with pro-inflammatory processes, it is important to remember that both enzymes also produce factors that inhibit or resolve inflammation and promote tissue repair (including the prostacyclins and lipoxins), The proper transition from the pro- to anti-inflammatory activities of the COX and LOX enzymes is an important for the progression of a healthy inflammatory response.