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Inflammation 101

Friday, February 17, 2012

Throughout most of human history, the main threats to human life and health have been the germ diseases: smallpox, bubonic plague, tuberculosis, dysentery, influenza, typhoid fever, etc. In the developed world these diseases have been mostly eradicated over the past century, and a new set of diseases have become the main causes of debility, illness and death.

The illnesses/conditions that plague the industrialized nations include allergies, asthma, age-related frailty, Alzheimer's disease and other dementias, arthritis, atherosclerosis, cancer, congestive heart failure, chronic fatigue/fibromyalgia, depression, diabetes, heart attack, inflammatory bowel disease, kidney disease, lupus, macular degeneration, osteoporosis, periodontal disease, overweight/obesity, skin disorders, stroke and surgical complications. 

Surprisingly, modern science has discovered a common denominator to all these conditions, and it isn't germs. It is inflammation. (1-8), (14-24), (43) And while germs may be considered enemy aliens who invade our bodies, inflammatory conditions are created by our own physiologic reactions. As Pogo wisely stated, "We have met the enemy and it is us."

Inflammation 101

Mosby's Medical Dictionary defines inflammation as "the protective response of body tissues to irritation or injury. Inflammation may be acute or chronic; its cardinal signs are redness, heat, swelling, and pain; often accompanied by loss of function.(9)

While acute (sudden onset) inflammation is often obvious (such as the redness, swelling, pain and tenderness from a cut), chronic inflammation, such as occurs in the linings of heart arteries in atherosclerosis, may have no visible or obvious signs or symptoms. Such "invisible" chronic inflammation may properly be called "silent inflammation."

Inflammation is an immune response, "designed" to protect us from germs, wounds or injuries. Without adequate inflammatory responses, life would not last long. Any germs invading our bodies would quickly overwhelm us. Wounds and injuries would not heal. New healthy tissues would not replace damaged tissue.

In a world without sanitation and full of germs, such as faced mankind prior to the 20th century (and still does today in the "underdeveloped" world), a vigorous inflammatory response is the key to health and longevity. A genetically weak inflammatory response would typically mean death in infancy from some germ disease.

Ironically, a genetically vigorous inflammatory response that is highly protective in a world of poor sanitation, full of germs, may serve to limit longevity in a world such as ours, where germs have mostly been conquered. This is because such vigorous inflammatory response tends to promote cancer with aging. (10)

The inflammation response involves a large cast of characters. White blood cells such as neutrophils, monocytes/ macrophages, basophils, eosinophils will speed to the inflamed area. (11) Cytokines, hormone-like immune proteins, will be secreted by various cells. Interleukin-1 and -6 and tumor necrosis factor-alpha are some of the most important inflammatory cytokines. (3) Tissue-swelling chemicals such as bradykinin, histamine and serotonin may be released. (11) Inflammatory prostaglandins and leukotrienes will further amplify the inflammatory response. (11)

In response to circulating interleukin-6, the liver will release acute phase reaction products, such as C-reactive protein and fibrinogen. (12), (13). In response to these pro-inflammatory biochemicals, white blood cells will secrete oxidants and free radicals to kill germs, and enzymes to dissolve dead and dying cells.

Unfortunately these oxidants and enzymes may harm healthy cells. The white cells may also burrow into tissues, such as artery linings, where they may cause unintended damage to the body's own tissues.

Eventually, other factors will turn off the inflammatory response as germs are disposed of and tissues begin to heal. If the inflammation response takes on a life of its own, becoming self-perpetuating, chronic inflammation develops. Chronic, "silent" inflammation is believed to be intimately involved in the development of obesity, insulin resistance, diabetes, cancer, heart disease, and Alzheimer's and other dementias. (14) (23).

Chronic Inflammation and The Modern World

In a healthy person the inflammation response is tightly controlled. It is only activated when there is a need from a germ invasion, a wound, tissue injury (such as a sunburn), a broken bone, etc.

Unfortunately, scientists have discovered that a host of factors all too common in the modern, developed world tend to promote out-of-control, chronic inflammation. Overweight/obesity (by some estimates over half of all Americans are overweight or obese), insulin resistance, sleep deprivation, hypokinesia (too little physical work/movement), mega-stress, aging, and improper diet are just some of the all-too-common promoters of chronic inflammation.(3), (10),(15), (16), (24), (25), (33) (35)

The Inflammatory American Diet

The typical American diet almost looks as if it were designed to promote chronic inflammation. The processed-food American diet, once rich in trans-fatty acids, produced when vegetable oils are hydrogenated. Margarines, salad dressings, chips and baked goods such as cookies and crackers are just some of the dietary sources of trans-fatty acids. Research has shown these abnormal fatty acids to be inflammation promoters. (28) (30). Any oils still labeled "partially hydrogenated" tend to be rich sources of trans-fatty acids.

A diet rich in rapidly digested sugars/starches (high glycemic), especially when consumed by those overweight and/or insulin resistant (and such a diet promotes overweight/insulin resistance), promotes inflammation.(31). The typical American diet is rich in carbohydrates, with roughly two-thirds of the average American's carbohydrates coming from inflammation-promoting high-glycemic foods, such as bread, soft drinks/sodas, cakes, cookies, quick breads, doughnuts, sugars/syrups/jams, potatoes, cereal and pasta. (32)

Advanced glycation end products (AGEs) also promote inflammation.(36), (37). While AGEs are formed in our bodies, especially when blood sugar is frequently elevated, (38) they can also be absorbed from the diet. (36) ,(37). A diet high in pre-formed AGEs can seriously elevate blood levels of various inflammatory mediators, including C-reactive protein, tumor necrosis factor-alpha, and vascular cell adhesion molecule.(36), (37). A low-AGE diet can lower these inflammatory bio-chemicals.(36), (37).

What promotes the formation of AGEs in food? High heat/prolonged cooking.(36), (37) Deep-fried foods, such as French fries, fried fish and shrimp, fried chicken, etc. are great sources of AGEs. Well-done meats (including typical fast-food burgers), overly-crisp bacon, indeed anything cooked with high heat or for prolonged periods provides an AGE-rich diet.

The Vegetable Oil Connection

A major contributor to chronic inflammation in modern America is the over-consumption of the vegetable oils associated with overly-processsed junk food, especially corn, safflower, soy, peanut, cottonseed, sunflower and canola oils. These oils are rich in the omega-6 fatty acid linoleic acid. (39), (40). In the body, unbalanced linoleic acid can be metabolized to arachidonic acid. (39) (40).

Arachidonic acid is the raw material from which the body makes a broad range of pro-inflammatory biochemicals. (39),(40). When arachidonic acid is processed by cyclooxygenase enzymes, inflammatory prostaglandins and thromboxanes can be produced. (39), (40). When arachidonic acid is processed by lipoxygenase enzymes, inflammatory leukotrienes can be produced. (40).

Vegetable oils are a recent addition to the human diet. They only came into widespread industrial production in the 1920s. Over the past 50 years, as the anti-cholesterol medical/dietary establishment has told Americans to reduce their saturated fat intake, it has hyped the intake of linoleic acid-rich vegetable oils.

The common use of vegetable oils has caused a historically unprecedented shift in the diet-induced inflammatory balance. Linoleic acid can metabolize to a powerful inducer of a pro-inflammatory micro-environment in the cells that line our arteries and veins. (41).

Not only does high linoleic acid intake promote elevated levels of inflammatory prostaglandins, thromboxanes and leukotrienes,(39), (40), but it can also activate other powerful inflammatory molecules, including tumor necrosis factor-alpha (which in turn activates the super-inflammatory interleukin-6 and nuclear factor kappa Beta, (41). Nuclear factor kappa Beta in turn has the power to turn on the genes that promote production of over seven other pro-inflammatory cytokines and biochemicals. (55).

Omega-3s and the Modern American Diet

The good news is that the dietary counterbalance to linoleic acid/arachidonic acid is provided by the omega-3 fatty acids, alpha-linolenic acid and the fish oil fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). (39), (40). EPA at adequate blood/cellular levels can reduce conversion of linoleic acid to arachidonic acid, and reduce the conversion of arachidonic acid to inflammatory prostaglandins, thromboxanes and leukotrienes. (40).

In the vegetable oil-rich typical American junk food diet of the past 50 years, the omega-6-to-omega-3 dietary ratio tends to be inbalanced. This is due both to a reduction of dietary levels of omega-3 fatty acids, as well as an increase of omega-6 fatty acids. (39), (40). Thus the severely imbalanced fatty acid profile of the typical modern American diet has profoundly shifted our cellular biology to a pro-inflammatory status.  The most biologically efficient way to balance fatty acid intake is to clean up your diet.  Popping excessive amounts of fish oil capsules to balance a high junk food diet does not promote good health.

Obesity and Inflammation

A majority of the American population is now considered overweight or obese. Recent research has established that obesity is a major contributor to the chronic inflammatory state. According to researchers Lee and Pratley, "Obesity is characterized by a chronic, systemic low-grade state of inflammation. Biomarkers of inflammation, such as the leukocyte [white blood cell] count, tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and C-reactive protein, are increased in obesity, associated with insulin resistance, and predict the development of type 2 diabetes and cardiovascular disease. It is now clear that the adipocyte [fat cell] is an active participant in the generation of the inflammatory state in obesity. Adipocytes secrete a variety of cytokines, including IL-6 and TNF-alpha, that promote inflammation. Moreover, recent studies suggest that obesity is associated with an increase in adipose [fat] tissue macrophages [white blood cells], which also participate in the inflammatory process through the elaboration of cytokines.(24).

A recent human study has shown that the blood levels of two key inflammation molecules, interleukin-6 and C-reactive protein, increase as obesity intensifies. (26). There is growing evidence that the inflammatory cytokines secreted by fat cells, such as interleukin-6 and tumor necrosis factor-alpha, promote increased obesity, as well as insulin resistance. (16), (25), (42). Interleukin-6 stimulates the liver to release C-reactive protein, (13) and there is evidence that high C-reactive protein levels promote the development of type 2 diabetes. (17)

Sleep Is Not A Luxury

A.N. Vgontzas and colleagues have done human research that makes it clear that sleep deprivation promotes a pro-inflammatory environment. (33) (35). "Sleep deprivation leads to sleepiness and daytime hypersecretion of IL-6.(34). In an experiment with 25 healthy, normal sleepers, Vgontzas and associates measured the effects of decreasing sleep from eight hours nightly to six hours nightly for one week. (35). They found that in both men and women, there was a 40-to-60-percent increase in interleukin-6 secretion, while in men there was also a 20-to-30-percent increase in tumor necrosis factor-alpha. They concluded "in young men and women [presumably healthier than most middle-aged and elderly people], modest sleep loss is associated with significant sleepiness, impairment of psychomotor performance, and increased secretion of pro-inflammatory cytokines.(35).
It is generally accepted that 50 to 75 years ago, most Americans slept eight-nine hours nightly. People in "underdeveloped" nations, without widespread access to artificial light, frequently sleep more than that. Recent surveys of Americans' sleep habits show that many Americans now rely on only six or less hours of sleep nightly. These Americans can look forward to a lifetime of gradually increasing inflammatory status. As Vgontzas and coworkers point out, "the idea that sleep or parts of it are optional should be regarded with caution." (35).

Aging and Inflammation

There are various biological changes that occur with aging that unfortunately tend to promote chronic inflammation. With menopause, women typically suffer a drastic decrease in circulating estrogens. During the generally more gradual andropause, men tend to suffer reduced free testosterone. The adrenal steroid DHEA also shows a steep drop with aging, (44) as does the pineal hormone melatonin. (45). Cortisol levels tend to increase with age, as do adrenalin/noradrenalin. (3). Unfortunately, all these changes tend to promote inflammation.

Interleukin-6 is one of the most powerful and significant pro-inflammatory cytokines. (3). It is secreted by a wide range of cells. (3) It promotes the liver's release of acute phase (inflammation) reaction products, including pro-inflammatory C-reactive protein and fibrinogen.(3), (13). (Fibrinogen, formerly considered only a pro-coagulation factor, is now considered an inflammatory factor, as well.(47)

Interleukin-6 promotes a wide range of pathology, including diabetes, (17) cancer, (10) age-related frailty, (4), (5) insulin resistance, (46) heart disease (Fig. 1), (20), (21), (47) osteoporosis, (3) the "euthyroid sick syndrome" (reduced T3 levels),3 rheumatoid arthritis, (3). Alzheimer's disease, (48), and obesity. (26). Interleukin-6 levels tend to increase with age. (3)

Estrogen and testosterone tend to suppress interleukin-6 secretion, but these hormones decrease after menopause and andropause (3). DHEA suppresses interleukin-6 secretion, but DHEA levels drop drastically from age 15 to 75. (44) Adrenalin and noradrenalin promote interleukin-6 secretion, and they tend to increase with age.(3) Thus, it is hardly surprising that interleukin-6 levels tend to increase with age.
Five-lipoxygenase is an enzyme that increases with aging. (45), (49). It converts arachidonic acid into the powerful inflammatory leukotrienes. (45), (49).
Leukotrienes promote cancer, (18) damage the brain, (45) promote asthma, (18) arthritis, (18) psoriasis (18) and ulcerative colitis. (18). They may also promote atherosclerosis.(56) The 5-lipoxygenase enzyme is activated by glucocorticoids (cortisol), (49) and inhibited by melatonin. (45), (49). Unfortunately, aging and interleukin-6 increase cortisol in humans, (3), (50) while melatonin decreases drastically with aging. (51).

Stress and Inflammation

Stress is almost the hallmark of modern life. Overwork, lack of sleep, loud noise, congested traffic, fear of crime, and worry over money are just some of the many routine modern triggers of stress. The stress response involves the release of adrenalin, noradrenalin, and cortisol from the adrenal glands. (50)

While occasional stress in not toxic, and may even have tonic-like effects, excessive, unremitting stress gradually wears out the machinery of life. (50) And as just noted in the preceding section, adrenalin, noradrenalin, and cortisol promote inflammation, through increasing secretion of interleukin-6 and promoting production of super-inflammatory leukotrienes. Chronic cortisol excess also promotes obesity, (42) and as previously noted obesity promotes secretion of several major inflammatory mediators.

According to a 2003 study, "Production of IL-6 and other pro-inflammatory cytokines can be directly stimulated by depression and other negative emotions and stressful experiences.(57)

A recent study found that among elderly persons experiencing severe chronic stress from home-caring for a spouse suffering Alzheimer's disease, the levels of serum interleukin-6 increased over the six-year course of the study at a rate 400 percent higher than among age-matched non-caregiver controls. (57) Thus a life of chronic, unrelieved stress will promote chronic inflammation as well.

Measuring Inflammation

There are many mediators of inflammation that are measured in scientific experiments. These include tumor necrosis factor-alpha, prostaglandins, thromboxanes, leukotrienes, interleukin-1 and -6, and nuclear factor kappa Beta, to name just a few. Yet only two tests are available for routine clinical use: C-reactive protein (52) and interleukin-6. (47)

hese two inflammatory markers have been shown to be strongly associated with many diseases and conditions related to inflammation, so their levels can provide useful information about one's inflammatory status. There is no absolute number for C-reactive protein or interleukin-6 that is ideal, but obviously in general the lower the measured levels are the better.

C-reactive protein can be elevated by acute infections and injuries, as well as chronic inflammation, so a complete medical examination to rule out current infections or other acute increases of C-reactive protein is the best way to get an accurate picture of one's chronic inflammation level through C-reactive protein testing. A level lower than 0.5mg/L is generally a good sign, while a level of 2 to 3 mg/L or more is cause for concern. (47)

Interleukin-6 is necessary for a functioning immune system, so some is necessary. A level below 0.93pg/ml is a generally good sign, while a level of1.50 pg/ml or above may be cause for concern. (47)

Biosyntrx Supports An Anti-Inflammation Lifestyle

Just as the typical American diet and lifestyle promotes chronic inflammation, a more sensible one can reduce inflammation. Getting regular vigorous exercise tends to reduce C-reactive protein. (27) Brisk walking after meals will tend to reduce insulin resistance and high blood sugar spikes, since exercising muscles can remove glucose from blood without insulin. (53) And reducing insulin resistance will reduce C-reactive protein and fibrinogen. (16) While many physicians assume that C-reactive protein is simply a general marker (indicator) of inflammation, there is a growing body of evidence that C-reactive protein can directly promote inflammation. (13), (54)

Getting seven to eight hours of sleep nightly is an important way to reduce interleukin-6 levels, one of the most powerful pro-inflammatory factors.(3),(35). Losing weight, especially of the "beer belly" variety, will reduce secretion of interleukin-6 and tumor necrosis factor-alpha. (25), (26). Substituting olive oil for linoleic acid-rich vegetable oils, while adding freshly-ground flax seeds and fresh cold-water fish to the diet will improve the omega-6-to-omega-3 balance in the anti-inflammatory direction. (39), (40) The same study that found that linoleic acid powerfully turned on inflammatory gene activity, also found that oleic acid, which makes up almost 80 percent of olive oil, tended to reduce inflammatory gene activity. (41)

Avoiding hydrogenated vegetable oils and canola oil, margarines and baked goods will seriously reduce pro-inflammatory fatty acids. Read food labels.  Eliminating deep-fried and overcooked foods will reduce dietary "glycotoxins" (AGEs), with consequent reductions in C-reactive protein, tumor necrosis factor-alpha, and other inflammatory mediators. (36), (37)

Seriously reducing the high sugar/ starch junk foods typical of the American diet will reduce C-reactive protein, especially in those overweight. (31) It will also reduce production of inflammation-promoting AGEs in the body caused by frequent blood sugar spikes. (38) Finding ways to reduce stress will tend to lower interleukin-6 and inflammatory leukotrienes.(3), (49)

Proper dental care to reduce gingivitis and periodontal disease will also reduce many inflammatory mediators. (43) Quitting smoking will reduce C-reactive protein and other inflammatory mediators. (13).

Meet your anti-inflammatory micronutrient needs by trying your best to consume the new recommendation of nine to thirteen servings of  multi-colored fruits and vegetables a day.  A serving is about one half cup.

James South, MA - with permission from VRP
Ellen Troyer, MT MA - Biosyntrx CEO / Chief Research Officer


Given that chronic inflammation is now referred to as " The Plague of Our Time" and given the role that inflammation plays in the development of degenerative disease including eye diseases, it is most fitting that we dedicate and attribute this Friday Pearl research to James South, MA., a noted biochemist in the field of nutritional medicine. James was deeply involved with international nutritional medicine research and was considered to be one of the leading nutritional medicine formulators in the world. He was a prolific science writer, and the editor-in-chief of the much respected Optimal Health Review. Unfortunately, he died a quick death from an aggressive brain tumor a few years ago.  He is missed by his world-wide colleagues including those at Biosyntrx and VRP.

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Clinical references available in the Biosyntrx office.