Health Diagrams III — Inflammation from Cell to Tissue

---All 200 Posts---

I have explained my perspective in diagrams of the relationship between diet, gut flora and disease:

Health Diagrams I — Gut Flora and Diet

and of the interaction between gut flora, the immune system and autoimmunity:

Health Diagrams II — Curing Autoimmunity and Allergies

Now I am discussing how inflammation, the foundation of most chronic diseases, begins at the cellular level and results in the classic symptoms of tissue inflammation: redness, heat, swelling and pain.

NF-kB is the Transcription Factor that Controls Inflammation Genes

Of the 23,000 human genes, about 1,000 on each of 23 chromosomes, five dozen, e.g. enzymes involved in nitric oxide (vasodilation and erection hormone), synthesis of heparin sulfate and prostaglandin synthesis from omega-6 fatty acids or cytokines (IL-1, IL-6, TNFa), are associated with inflammation.  These inflammatory genes are turned on or expressed in individual cells, when the inflammation transcription factor, NF-kB, is activated by any of numerous external signals, including inflammatory cytokines, bacterial or fungal cell wall materials (LPS or beta-glucan), advanced glycation end products (AGE, e.g. HgA1C, resulting from high blood sugar) or reactive oxygen species (ROS, e.g. super oxide, from insulin resistance).

NF-kB and Inflammation
Superoxid Causes Insulin Resistance

Inflammation is the Foundation of Growth, Birth, Cancer and Pain

We think of inflammation as the sum of physical symptoms, and our purpose in responding to inflammation is typically to limit its impact.  We try to stop swelling by applying cold or hot, and we take aspirin to lower fevers and stop pain.  We fail to realize that inflammation is essential to the growth and development of many different tissues, and that inflammation is a cycle that leads back to normal function.  

Body tissues, such as the lining of the intestines or the uterus, continually produce new cells to replace the old that are sloughed off.  NF-kB must be turned on for these growth and attrition cycles.  Taking aspirin blocks NF-kB in the gut and stops local development of the lining, resulting in weak areas that bleed.  That is why doctors encourage patients to drink a half glass of water before and after swallowing aspirin tablets. 

Another more dramatic example of control of inflammation is conception, gestation and birth.  Conception and gestation require inhibition of inflammation, to permit growth of a foreign organism (a fetus is half sperm genes) in the uterus.  Chronic inflammation limits the ability of the uterus to suppress immune attack and can produce infertility, which is treated by aspirin and heparin, which suppress chronic inflammation.  The return of inflammation at the end of gestation precipitates labor and birth.  Excess Inflammation produces high levels of circulating inflammatory cytokines, which causes postpartum depression.  Depression and chronic inflammation have the same cytokine profiles, i.e. depression is a symptom of chronic inflammation.

Birth and Inflammation

Proliferation, or enhanced cell division, is another aspect of inflammation and is also the foundation for cancer.  That is the reason that some doctors recommend low dose aspirin to reduce colon cancer.  Similarly, since inflammation is the basis for coronary artery disease, doctors sometimes recommend low dose aspirin, although this is controversial.  Doctors also use aspirin as a so called blood thinner, since it blocks inflammatory signaling in platelets and discourages clotting.  Inflammation of nerve cells is experienced by the brain as pain.  

When it is understood that inflammation is an essential feature of many normal, healthy cell and tissue functions, then “inflammation," with its negative connotations, becomes a misnomer.

NSAIDs Inhibit Inflammatory Prostaglandin Production

Aspirin directly inhibits NF-kB activation inside the cell, but it also chemically modifies COX, the enzyme that converts omega-6 polyunsaturated fatty acids (common in polyunsaturated vegetable oils) into inflammatory prostaglandins.  Other NSAIDS (Non-Steroidal Anti-Inflammatory Drugs) just inhibit COX, but Aspirin transfers its acetyl group to make acetyl-COX, which has a new activity that converts omega-6 fatty acids into anti-inflammatory prostaglandins.  The high omega-6 fatty acid content of vegetable/seed oils, such as corn, soy, canola, etc. is why these oils, in contrast to olive oil or butter, are inflammatory.  Omega-3 fish oil is anti-inflammatory, because it is converted to anti-inflammatory prostaglandins.  Plant omega-3 fatty acids are shorter and are not converted to prostaglandins, but inhibit omega-6 conversion.

Aspirin

Nitric Oxide, Vasodilation and Viagra

Swelling is caused by vasodilation, the relaxation of blood vessels, and accumulation of serum in the tissue.  This vasodilation also makes the tissue red and warm from the increased amount of warm blood in the capillaries.  Vasodilation is caused by nitric oxide, NO, that is produced by an enzyme under the control of NF-kB, which takes the nitrogen from arginine (or nitroglycerine).  The NO diffuses easily and binds to receptors that produce an amplified signal, cyclic GMP, that relaxes the muscle cells surrounding blood vessels.  [Viagra is potentially dangerous, because it just exaggerates the amplified signal and obscures the underlying vascular damage, e.g. hypertension, that causes erectile dysfunction by blocking normal vasodilation.]

Nitric Oxide and Erectile Dysfunction

Hot/Cold and Endorphins

The dilemma of whether to use hot or cold therapy to block inflammation is based on a misunderstanding of what the temperature changes are actually doing.  Changing the temperature of the skin alters the structure of sensory proteins in nerves of the skin and triggers signals to the brain that register as hot or cold.  Chemicals, e.g. capsaicin or menthol, can have the same effect without changing skin temperature.  The important response for inflammation control, is return signals from the brain that release neurohormones, e.g. endorphins, from different nerves that reach not only some of the skin that was hot or cold, but also deeper tissue.  The endorphins block inflammation and all of its symptoms.  That is why chemically treated pads are more effective than icing or changing from hot to cold, because "hot" and "cold" signaling chemicals can be applied simultaneously.  None of the treatments is more than skin deep.  Actually chilling or heating tissue below the skin is damaging and causes more inflammation.  Low dose Naltrexone may be effective in some cases of chronic inflammation, by stimulating systemic rebound endorphin production.

Dr. Oz, Pain, Hot/Cold Receptors

Lymphocyte Offloading, Mast Cells, Heparin

Rosacea is a group of diseases that involve inflammation of the face in an exaggerated blush.  Any of the signals that would lead to blushing cause intense vasodilation.  A blush is fleeting, but rosacea is made chronic by another aspect of inflammation, offloading of lymphocytes.  Large numbers of lymphocytes accumulating in response to a local infection would produce pus.  In the case of rosacea, the distributed leucocytes, including neutrophils, respond to the blushing signals by producing inflammatory signals, such as P protein.  The result is cycles of inflammation, autoinflammation.

Mast cells can also be offloaded from blood vessels and provide a link between the immune system and inflammation.  Mast cells display IgE receptors on their surfaces, which bind antigens and trigger release of histamine, heparin and protease.  Histamine is a neurotransmitter that binds to receptors on blood vessels and nerve cells.  In the gut, histamine mediates many digestive processes.  Heparin released along with  histamine, coats the gut and prevents attachment of pathogens by competing for binding to the heparan sulfate proteoglycans (HSPGs) that form the surface of cells that line the gut.  [Heparin is the most common drug used in hospitals and is produced from intestines of cattle and hogs in the meat industry.]  Heparin also binds and inactivates the proteases released from mast cells.  Upon release, the now active proteases attack and activate receptors on nerves and immune cells.

Mast Cells and Heparin

Heparin is Anti-Inflammatory

Heparin is the most negatively charged polysaccharide, mediates most of the receptor/hormone interactions at cell surfaces; facilitates amyloid plaque formation, e.g. in Alzheimer's, atherosclerosis, diabetes, dementia; and controls numerous protease reactions in the complement system and clotting, etc.  There are hundreds of heparin-binding proteins.  Heparin is produced in secretory granules of mast cells by the action of heparanase on heparan sulfate proteoglycans. Heparin is a mixture of small fragments, oligosaccharides of heparan sulfate polysaccharides.  Heparin is anti-inflammatory and is administered to facilitate conception and gestation.  Inflammation also inhibits the genes involved in heparan sulfate proteoglycan production and since HSPGs are a major component of basement membranes of tissues and provide the barrier function of blood vessels in kidneys and brain, inflammation leads to proteinuria and loss of the blood brain barrier.  Since HSPGs have a short half life of six hours and are rapidly recycled, heparin added to the blood is rapidly absorbed by vessels, and heparin taken orally is absorbed by intestinal cells, but does not reach the blood.  HSPGs and heparin are central components of immunity and inflammation.

Heparin and Inflammation

Inflammation Blocks Skin Synthesis of Vitamin D from Cholesterol

Inflammation blocks solar synthesis of vitamin D in the skin and is more important than skin pigmentation, use of sunblock or latitude in producing vitamin D deficiency.  The vitamin D content of food is negligible compared to solar production in the skin.  It is not surprising that rising chronic inflammation is also accompanied by rising vitamin D deficiency.  Vitamin D supplementation is usually ineffective in curing vitamin D deficiency, because the supplements are too low and very high levels of supplemental vitamin D are required to reverse underlying chronic inflammation.  Statins are very effective at blocking cholesterol synthesis and although reducing cholesterol has minimal impact on the target, cardiovascular disease, it dramatically reduces vitamin D causing muscle pain, etc.

Most vitamins are enzyme cofactors synthesized by gut bacteria and used as quorum sensing signals during formation of biofilms.  Vitamin D, in contrast, is a steroid hormone and receptors for vitamin D are inside cells.  The receptor/vitamin D complex is transported into the nucleus where it acts as a transcription factor to control the expression of genes.  Vitamin D controls the expression of defensins in the crypts of the villi of the small intestines.  The antimicrobial activity of defensins is based on the basic amino acids (arginine and lysine) of its heparin binding domains.  Vitamin D also interacts with NF-kB in the nucleus and modulates inflammation.

Inflammation and Vitamin D

Bacteria and LPS

Lipopolysaccharide is a wall component that is indicative of bacteria, just as beta-glucan is indicative of fungi, and both are intense activators of NF-kB and inflammation.  LPS is released from damaged bacteria, e.g. by antibiotic treatment, binds to receptors on the surface of intestines and stimulates inflammation with release of NO, which produces diarrhea.  Food intolerances, which are based on incomplete digestion of food components, because of an incomplete gut flora (immunological responses/food allergies are rare) are probably also the result of LPS release from gut flora and inflammation.

Innate Immunity is also Triggered by LPS

The basic defenses of humans against microorganisms are mediated at the cellular level by triggering molecules common to all microorganisms, e.g. LPS for bacteria.  The responses are equally general: lysozyme to digest bacterial wall peptidylglycan, lactoferrin that binds iron and yields antibacterial peptides.  LPS (and inflammatory cytokines) also stimulates the liver to produce CRP (C Reactive Protein) that binds to choline on bacteria as the first step in phagocytosis and DNAse I that digests NETs (neutrophil extracellular traps) that are the DNA and histones released by triggered neutrophil cells that enmesh bacteria for engulfment by phagocytic cells.  [NETS plug peripheral catheters and can be cleared with probiotics that stimulate DNAse I release from the liver.]  NETs are also present at sites of inflammation and the accompanying nuclear proteins have the basic triplets that stimulate immune presentation and act as autoantigens, i. e. produce anti-nuclear antibodies, in the absence of adequate Tregs.

Diet and Inflammation

The diagram outlines the interactions that produce the tissue symptoms of inflammation.  Many components of modern diet can trigger inflammation:

Sugars and high glycemic starches raise blood sugar and enhance AGE/HgA1C.

Vegetable oils high in omega-6 oils are converted into inflammatory prostaglandins.

Wheat and other grains have high glycemic starch and insoluble fiber that is inflammatory.  Gluten is inflammatory.

Antibiotics damage the gut flora and produce vitamin deficiencies, autoimmunity and allergies.

Food intolerances result from damaged gut flora and produce gut inflammation.

Fish high in omega-3 EPA and DHA are anti-inflammatory.

The Anti-Inflammatory Diet

Health Results from a Balance of:

Diet (meat, fish, eggs, dairy, vegetables), containing macronutrients of protein, starch 30-100 g/d and fat (low omega 6/3 and saturated fat for most calories), and micronutrients

Soluble Fiber, e.g. resistant starch (consult Free the Animal), inulin, pectin, (plant polysaccharides, animal GAGs)

Gut Flora, diverse and adapted to dietary soluble fiber,

Exercise

Resistant Starch, Panacea, but Why?

Mark’s Daily Apple provides an authoritative diet guide (except for the gut flora).

Transglutaminase, Gluten, Celiac, Inflammation, Autoimmunity

The point of this post is that the intestines produce an enzyme, transglutaminase (TG) that normally protects the gut from toxic plant proteins, such as grain gluten, but modern food processing and antibiotics corrupt digestion of gluten to produce intestinal inflammation and a series of related autoimmune diseases including celiac, thyroiditis, diabetes, baldness and atherosclerosis. 

Transglutaminase Links Proteins Enzymatically

Transglutaminase is a ubiquitous enzyme produced in the intestines, thyroid, heart, skin, hair follicles, etc.  This enzyme attaches to a protein (TG + ProA ~~> TG-ProA) via amino groups extending from some of the protein's amino acids, e.g. lysine or glutamine, and then the enzyme replaces itself by another protein leaving the two proteins crosslinked (TG-ProA + ProB ~~> TG + ProA-ProB).  Another alternative reaction is to leave the original glutamine without its amino group to yield glutamic acid residues.

Linking Proteins Makes Connective Tissue Tough

Transglutaminase is useful to crosslink the proteins in connective tissue.  Proteins in basement membranes form a matrix by binding to the heparan sulfate sidechains of another basement protein, perlecan.  The heparin-binding domains consist of basic amino acids that TG can react with to crosslink the proteins.

Linking Pathogen Proteins

Transglutaminase is also produced to crosslink the DNA/heparin/matrix polysaccharide-binding domains of pathogenic bacteria leading to aggregation, localization and death of the bacteria.  Inflammation resulting from activation of the inflammatory transcription factor, NFkB, stimulates production of TG.

Gluten is a Plant's Way of Saying "Don't Eat Me!"

Gliadin is a protein component of gluten that contains long stretches of glutamine residues, i.e. it is a polyglutamine protein similar to the protein that causes Huntington's disease.  Gliadin is an advantage as a storage protein for grain, because it is aggregated by the TG that protects the lining of the intestines of herbivores, such as humans, makes the animal sick and thereby discourages eating the grain.  Aggregation of gliadin/gluten inhibits digestion of the grain protein and can leave TG bound to gliadin.  Conversion of the polyglutamine stretches to polyglutamic acid stretches that are negatively charged, produces proteins that will bind to the positively charged heparan sulfates that circulate along the surface of intestinal cells leading to damage and inflammation.

Basic Triplet Leads to Antibody Production

Transglutaminase is also transported into cells, because it contains a region with a triplet of basic amino acids (...EPKQKRKLVA...).  This internalization probably contributes to enhanced presentation of TG to the immune system for subsequent antibody production.

Transglutaminase is Inflammatory

Transglutaminase interaction on the surface of cells also activates, NFkB, the transcription factor responsible for inflammation. Thus, TG turns on inflammation and part of inflammation is the activation of the innate immune system that includes production of TG.  This circular activation may produce autoinflammation that is associated with various forms of inflammatory bowel diseases.

Gluten Sensitivity is Normally Controlled By Gut Flora

Gluten sensitivity expressed by most people, is the intestinal response to the toxicity of gluten as it interacts with TG and causes inflammation.  This inflammation will also result in immune presentation of both gliadin and TG, and production of antibodies to both. Antibody production will normally be controlled by regulatory T cells of the immune system, unless spreading inflammation in the gut and/or antibiotics destabilizes the gut flora and compromises regulatory T cell development in the intestines.  

Anti-Glutaminase Antibodies Attack the Gut

Celiac results from uncontrolled production of antibodies to gliadin and TG with attack by the immune system on the aggregated gliadin/TG on the surface of the intestinal epithelium.  Celiac flare ups in response to eating even small quantities of gluten lead to further inflammation of the gut and further disruption and simplification of gut flora.

Celiac Leads to Thyroiditis and Much More

Transglutaminase is also produced by the thyroid and celiac will develop into a more generalized autoimmune disease that results in Hashimoto's thyroiditis.   TG production in the skin can result in skin rashes and may contribute to rosacea.  The base of hair follicles contains TG involved in hair production, and may contribute to some forms of hair loss.  Another substantial worry about the sequelae of celiac and gluten intolerance is the presence of TG in coronary arteries.

Antibiotics are Part of the Gluten Problem

Celiac and gluten sensitivity seem to be increasing with modern processing of grains and increased use of antibiotics.  Wheat has been gradually changed by traditional breeding, but genetic engineering has not yet been developed for wheat.  So, at least in this case, GM wheat cannot be part of the problem.  Many recent studies show that antibiotics profoundly and permanently alter gut flora.  As a result, the immune system, which is dependent on gut flora diversity is compromised, and various forms of autoimmunity and allergies develop.

Super Fine Flour Damages Gut Flora

Germ and bran are removed from all wheat before it is ground.  This is true even for whole grain flours, which have some of the germ and bran added back after milling.  Modern milling may be part of the gluten problem, because the flour is ground so fine that the grains of starch are broken.  Broken starch grains are digested by pancreatic amylases in the upper intestines, whereas some of the starch from intact grains is digested by gut flora in the colon.  Thus, modern wheat flour fails to feed gut flora like soluble fiber to produce short chain fatty acids, e.g. proprionic acid that supports Treg development; modern superfine flour supports autoimmune diseases and allergies.

Cultural Practices Make Gluten Safe

Wheat has been bred to produce bread as fast as possible from superfine flour.  This rapid bread production eliminates the exposure of gluten to enzymes from both germinating wheat seed and fermenting bacteria, which are part of traditional bread making.  Coarsely milled, traditional flour responds to soaking in water by activating enzymes that partially digest gluten, since gluten is a storage form of amino acids destined for the seedling.  Sour dough starter, a mixture of bacteria that can ferment the starch and gluten into short chain fatty acids and bubbles of carbon dioxide, has been used traditionally to provide leavening and flavor to bread.  Both flour and bacterial enzymes modify the structure of gluten to render it less toxic to the intestines.  Cultural traditions insured that gluten would be systematically detoxified by enzymes during hydration and fermentation of dough prior to baking.  Modern processing leaves wheat gluten in bread unmodified and toxic.

Prevention and Cure:  Eliminate or Detoxify Wheat and Add Bacteria

Preventing and curing diseases associated with gluten and transglutaminase is simple.  Eliminating wheat would do the trick.  Unfortunately, wheat is the mainstay in many parts of the world.  Fortunately, gluten intolerance is not uniformly observed where wheat is eaten.  This indicates that there are potentially safe ways to eat wheat and bread.  I gained insight into how to eat wheat safely from two books that were recently published:  Cooked by Michael Pollan and Artisan Bread in Five Minutes a Day by Jeff Hertzberg, MD and Zoë François.

Michael Pollan has recently become interested in gut flora and his book revealed how he built up a healthy gut flora eating homemade fermented food and compromised his work with antibiotics.  The major breakthrough that I made by reading Cooked was based on his experiments in baking whole wheat bread.  He hydrated the flour first and then used sour dough starter for lengthy fermentation.  This was the same process that I had used to make great loaves of bread (photo above) using Jeff Hertzberg’s directions in Artizan Bread in Five Minutes a Day.

The answer to gluten intolerance and most autoimmune diseases amounts to eliminating wheat or treating wheat in a safe, traditional process that inactivates the toxic properties of gluten; and maintaining a healthy gut flora (probiotics are not enough) with hundreds of different species of bacteria that promote the development of the suppressive immune system mediated by regulatory T cells:

Safe Traditional Bread 

• Remove bran and discard as toxic insoluble fiber.
• Grind wheat to retain starch grain structure.
• Soak flour to hydrate and activate wheat enzymes to start digestion/detox of gluten.
• Ferment dough with bacteria (sour dough starter) to continue digestion/detox of gluten.
• Bake.

Develop Healthy Gut Flora and Suppressive Immune System

• Avoid antibiotics that kill bacteria.
• Avoid hygiene practices, e.g. antibacterial soaps, bleaching surfaces, closing toilet covers, etc. that eliminate sources of healthy bacteria.
• Kiss your loved ones and pets, and encourage everyone to garden/play in the soil (an excellent source of thousands of different species of bacteria.)
• Recruit healthy gut bacteria by eating a variety of homemade fermented vegetables. My most highly recommended source is my friends at: http://www.fermentista.us
• Remember that cooked or pasteurized foods do not contain useful bacteria.
• Remember that dairy probiotic bacteria cannot live in the human gut and can only provide a temporary help to the immune system.
• Limit the variety of foods that are consumed and gradually change with the seasons to avoid rapid changes in nutrients to which gut flora cannot adapt.  Food intolerances indicate maladapted gut flora.
• Constipation indicates dysfunctional gut flora and a compromised immune system.

Psoriasis, IL-17, Cathelicidin, TLRs, NFkB, Inflammation and Heparin Therapy

Host DNA Released by Keratinocyte Apoptosis Binds LL-37 and Activates Dendrocytes

Psoriasis is an inflammation of the skin that leads to overproduction of keratinocytes resulting in a thick crust.  Skin inflammation, in this case, is considered a result of autoimmunity, but an autoantigen has not been identified.  It is more likely that psoriasis results from an autoinflammatory condition, in which inflammation produces a complex of self molecules that mimic bacterial DNA and trigger TLR/NFkB inflammation signaling.  And of course, if this is going to be interesting, it has to involve heparin.

Vitamin D Binds to a Transcription Factor Receptor that Controls Antimicrobial Peptides
A significant component of the innate immune system is a group of antimicrobial peptide  (defensins, cathelicidins, e.g. LL-37).  These short polypeptides owe their natural antibiotic activity to numerous basic (positively charged, arginine and lysine) amino acids.  The transcription factor that controls the expression of these peptides is the vitamin D receptor.  Thus, various forms of vitamin D influence the amount of antimicrobial peptides produced in the mouth, skin and crypts of the intestinal villi.  Oral vitamin D3 would be expected to directly improve defensin production in the gut and LL-37 production in the skin.

IL-17 Stimulates Skin Inflammation and LL-37 Production
A specific group of lymphocytes, called T helper 17 cells, produce IL-17.  These Th17 cells accumulate in some sites of inflammation, such as psoriasis and their secretion of IL-17 is associated with ongoing inflammation and may contribute to LL-37 production, as well as apoptosis of keratinocytes in the thickening skin of psoriasis plaques.
http://www.ncbi.nlm.nih.gov/pubmed/19623255?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_SingleItemSupl.Pubmed_Discovery_PMC&linkpos=2&log$=citedinpmcarticles&logdbfrom=pubmed

Th17 Cells Are Produced in the Gut in Response to Segmented Bacteria
One of my readers brought to my attention an article that shows that one of the hundreds of species of gut bacteria, segmented filamentous baceria, stimulates the gut to develop T helper 17 cells that subsequently migrate to sites of inflammation.
http://www.medpagetoday.com/Gastroenterology/InflammatoryBowelDisease/16472
This emphasizes the link between the gut and inflammatory diseases and parallels other examples of gut influence on disease, such as the ability of Helicobacter pylori to affect asthma or parasitic worms to tame Crohn’s disease, allergies and asthma.

Inflammation Lowers Heparan Sulfate Production and Spreads LL-37
One of my students induced inflammation in cells in vitro and showed by quantitative PCR that genes involved in heparan sulfate proteoglycan production are selectively silenced.  This observation explains in part the loss of heparan sulfate in kidneys and intestines that contributes to the leakiness of these organs in response to inflammation and the partial repair of these organs by heparin treatment.  Decrease of heparan sulfate that normally coats cells and binds antimicrobial peptides, such as LL-37, would explain the enhanced movement of LL-37 in psoriatic skin.

LL-37 Binds to Host DNA and Triggers Toll-Like Receptors
DNA is released from keratinocytes in psoriatic skin and this host DNA binds the antimicrobial peptide cathelicidin LL-37.  The LL-37/DNA complex mimics bacterial DNA and triggers the Toll-like receptors (TLR) on the surface of immune cells, dendrocytes, to activate NFkB, the transcription factor controlling inflammation.
http://www.ncbi.nlm.nih.gov/pubmed/19050268?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_SingleItemSupl.Pubmed_Discovery_RA&linkpos=1&log$=relatedarticles&logdbfrom=pubmed

Heparin Treats Psoriasis
It seemed obvious to me that the heparin binding domains (Look at all the basic amino acids in blue in the illustration of LL-37.) of LL-37 were involved in DNA binding and the reason the LL-37 was binding to host DNA, was that heparan sulfate had been depleted as a result of local inflammation.  It also seemed obvious that topical heparin should eliminate psoriasis plaques.  So I did a Google search of psoriasis + topical heparin and got a hit on a 1991 patent application that claims a broad applicability for heparin use in curing symptoms of a wide variety of diseases, including psoriasis.
http://www.patentstorm.us/patents/5037810/description.html
The only topical form of heparin that I know of is Lipactin (available in Canada and Europe?), a treatment for coldsores, which makes sense because herpes viruses use heparan sulfate to infect cells.

Cytstic Fibrosis Overproduces Tissue Transglutaminase and Contributes to Celiac

Tissue transglutaminase (tTG or TG2) is produced in excess in some diseases, such as cystic fibrosis, and contributes to inflammation and disease symptoms. tTG also readily moves in and out of cells by virtue of its basic triplet and when in the cytoplasm, tTG is ubiquinated and degraded by proteosomes. I have previously pointed out that internalization and proteosome degradation are also the initial steps in processing of proteins for presentation by the immune system and antibody production, i.e. turning a cellular protein into an autoantigen involved in autoimmune disease.

Here is an image of a computational protein model of tTG I drew with Chimera. I have highlighted the basic triplet to show its exposure to facilitate transport.

Oxidative Stress Alters tTG and Triggers Inflammation

A recent article also links tTG intracellular chemical modifications (SUMOylation), which are linked to oxidative stress, to activation of NFkB and inflammation. Thus, tTG is a major player in controlling cell surface interactions with potentially toxic materials such as polyglutamine-rich gliadin, as well as triggering inflammation in response to oxidation stress.

Cystic Fibrosis Causes Overproduction of tTG

When I read that cystic fibrosis results in an increase in the production of tTG in lungs, I immediately thought of the role of tTG as an autoantigen in celiac disease and the progression of celiac into Hashimoto’s thyroiditis, which has the same autoantigen, tTG. I suspected that the overproduction of tTG and inflammation in cystic fibrosis should increase tTG autoantibody production and tTG-mediated autoimmune diseases of celiac and Hashimoto’s thyroiditis.

Extra tTG Leads to Autoimmune Celiac

A quick PubMed search of CF and celiac, revealed a study of comorbidity between CF and celiac in Norway. Just as expected, the two diseases occur together with a frequency three times higher than predicted by coincidence. CF stimulated tTG overproduction was driving the development of celiac.

references:
Luciani A, Villella VR, Vasaturo A, Giardino I, Raia V, Pettoello-Mantovani M, D'Apolito M, Guido S, Leal T, Quaratino S, Maiuri L. SUMOylation of tissue transglutaminase as link between oxidative stress and inflammation. J Immunol. 2009 Aug 15;183(4):2775-84.

Fluge G, Olesen HV, Gilljam M, Meyer P, Pressler T, Storrösten OT, Karpati F, Hjelte L. Co-morbidity of cystic fibrosis and celiac disease in Scandinavian cystic fibrosis patients. J Cyst Fibros. 2009 May;8(3):198-202.

Vagus Nerve Controls Gut Inflammation II

Inflammatory Mast Cells Silenced

In a previous article, I outlined the role of the vagus nerve in responding to infection/damage signals by producing signals that inhibit inflammation. In a recent article (ref. below), the role of the vagus nerve in gut inflammation was examined using real-time biophotonic labeling. Basically that means that a video camera sensitive to infrared can be used to detect infrared dyes produced when NFkB is activated -- the camera is able to visualize regions of inflammation in living mice. Using this technique, researchers were able to demonstrate that cutting the vagus nerve produced heightened inflammation in gut treated with an irritant. The vagus nerve appears to stimulate regulatory T cells that lower the activity of inflammatory cells.

Inflammation/NFkB Activation Visualized in Live Mice

The studies were performed in a mouse line constructed to express an infrared fluorescent protein in cells in which the inflammation transcription factor, NFkB, is activated. Mice of this strain were prepared with and without the vagus nerve intact leading to the intestines. The mice were then exposed to sodium dextran sulfate (DSS) to simulate inflammatory bowel disease symptoms.

Cutting the Vagus Nerve Permits Inflammation

Mice with intact vagus nerves exhibited much less inflammation in their gut than those without vagus innervation. The cut vagus experiments demonstrated that the vagus nerve was responsible for suppressing inflammation. Further experiments were performed to determine if the inflammatory and anti-inflammatory reactions could be transferred to other mice by transferring cells from the treated mice.

Regulatory T Cells (CD4+, CD25+) Block Inflammation

Transfer experiments showed that inflammatory T cells (CD4+, CD25-) from cut vagus, DSS mice would cause bowel inflammation in other mice, but that did not happen with the same type of cells from mice with intact vagus nerves. Further tests showed that either cutting the vagus or adding inflammatory T cells from a mouse with a cut vagus, reduced the population of regulatory T cells (CD4+, CD25+) in control mice treated with DSS. So, without the vagus stimulation, the regulatory T cell population declined in the presence of inflammatory signals.

Absence of Regulatory T Cells Can Explain Many Inflammatory Diseases

In many inflammatory diseases, e.g. celiac, Crohn’s disease, rosacea, there appears to be a deficiency of regulatory T cells. In the absence regulatory T cells, signals from vagus nerves will no longer produce anti-inflammatory suppression. In fact the same nerve signals may become inflammatory. This would explain why rosaceans will become inflamed by hot or cold stimulation that would normally lead to anti-inflammatory stimulation of regulatory T cells. Similarly, capsaicin, castor oil and menthol, which normally produce an anti-inflammatory response, produce inflammation in rosaceans.

[Vagal stimulation exercise links:  here and here.]

reference:
O'Mahony C, van der Kleij HP, Bienenstock J, Shanahan F, O'Mahony L. 2009. Loss of vagal anti-inflammatory effect - in vivo visualization and adoptive transfer. Am J Physiol Regul Integr Comp Physiol. Aug 12. [Epub ahead of print]

Inflammation and Vitamin D Deficiency

Does Dietary Inflammation Reduce Skin Production of Vitamin D?

The media discovered the vitamin D deficiency pandemic last week. Amazingly researchers were recorded on camera saying that the D deficiencies are caused by insufficient exposure to ultraviolet in sunlight and inadequate consumption of vitamin D-laced milk. Have all of these people been avoiding the biomedical journals?

Have they noticed that my tan improved since I started eating anti-inflammatory?

Let’s shine some sunlight on these knowledge deficiencies:

• Serum vitamin D levels have been dropping (as chronic inflammation has been increasing) over the last three decades -- has something changed in our diets?
• Vitamin D deficiencies occur globally (not restricted to Northern latitudes or winter) -- related to diet?
• Women are more vulnerable, because of cultural modesty in some countries, but males are still D-deficient.
• A subset of people exposed to ample sunshine are still D-deficient.
• Vitamin D deficient individuals also have elevated TNF.
• Vitamin D deficiency and inflammation are risk factors in the same diseases.

It seems that the simplest conclusion is that chronic inflammation leads to vitamin D deficiency, even though vitamin D deficiency may also contribute to inflammation.

This also probably means that chronic inflammation makes it harder for skin to produce vitamin D during exposure to sunlight.

One would expect those who are inflamed to get sunburned more readily and people who eat plenty of omega-3 rich seafood probably produce more vitamin D, even if they are not in the sun as much.

Inflammatory starvation (or American fast food) diets high in starch and omega-6 vegetable oils, should produce vitamin D deficiency even on the Equator.

We should not be surprised that inflammatory degenerative diseases are associated with vitamin D deficiency. It would be interesting if vitamin D supplementation to eliminate deficiency, reduced inflammation and reversed degenerative disease.

Do statins reverse vitamin D deficiencies (and improve tanning) as they lower inflammation? [Statin lowering of LDL is unrelated to reduction in cardiovascular disease. Only the anti-inflammatory side-effect is important.]

Does NFkB activation (inflammatory signaling) inhibit vitamin D receptor activity and vice versa?

You can forget all of this confusion, if you just stick with an anti-inflammatory diet (that includes vitamin D supplements) and exercise frequently in the great outdoors.

Brilliant Blue Brains and Spinal Cords

Hibernation-Suppression and Trauma-Induction of Inflammation

Inflammation/hibernation is a complex story at the foundation of chronic diseases. Inflammation is the common thread -- activation of the inflammation transcription factor NFkB.

Trauma Causes Life-Threatening Trauma

Trauma, everything from a bee sting to a horrific traffic accident that causes head and spine injuries, results in initial tissue damage and subsequent inflammation damage. The inflammatory response to punctures and abrasions is usually appropriate and self-limiting. The immune response to serious injuries is frequently more life-threatening than the initial damage.

Transplanted Organs Suffer from Inflammation

Organs removed for transplantation are subjected to a certain amount of necessary trauma and oxygen deprivation. If the organ was simply popped into a waiting recipient biochemically unaware of the process, the initial damage would be readily repaired in its new home. Unfortunately, some of the organs overreact and become damaged by their own immune/inflammatory reaction to the surgery.

Hibernation Reduces Trauma Inflammation

Organ transplants between animals that are hibernating, are much more successful, because the damaging inflammation is suppressed. Hibernation in animals or in human organs can be induced by the use of opioid peptides, e.g. DADLE, and subsequent surgical procedures are more successful. Hibernation also provides protection against experimental stroke. Apparently, the activation of the opioid receptor suppresses activation of NFkB and avoids inflammation.

Opioids and Steroid Hormones Block NFkB Activation and Inflammation

Steroid hormones can also provide protection against inflammatory damage resulting from head trauma. Thus, the ubiquitous steroid receptors may also block NFkB activation and inflammation.

Trauma Releases ATP that Triggers P2X7 and NFkB

Extracellular ATP can activate NFkB activity and inflammation, and ATP accumulation at trauma sites may be particularly dangerous for spinal injuries. Inhibitors of ATP binding to the purinic receptor P2X7, block inflammation and provide dramatic improvement in the return of function in animal models of spinal injuries. Most of the common inhibitors of P2X7 signaling must be injected directly into the traumatized tissue to block inflammation, because they can’t cross the blood-brain barrier. An exception is Brilliant Blue G.

Brilliant Blue G Blocks Trauma Inflammation

Brilliant Blue G, a.k.a. Coomasie Brilliant Blue, should be very well known to molecular biologists, because it is the commonly used stain for proteins separated on SDS-PAGE gels. I used that dye literally thousands of times to stain gels and I even tried it to stain the extracellular matrix surround cartilage-secreting cells, chondrocytes, grown in culture. I have included one of those pictures just for old times sake.

BBG can be injected IV into mice and the result is amazing. Not only do the mice become blue, but they recover much better from experimental spinal trauma. BBG in the blue mice blocks inflammation due to the surge in tissue ATP and the mice heal their trauma and regain function.

It would be amazing if BBG worked on people with spinal injuries. I expect the rapid development of a suitable drug to help spine and head trauma patients.

Can Manipulation of Hibernation Cure Chronic Diseases?

A big question is whether or not similar drugs might be used to block inflammation that supports cancer and other forms of chronic illness. Alternatively, in some instances the problem is that bacteria are suppressing local inflammation and inducing tissue hibernation to produce chronic illness. Under these circumstances, the induction of local inflammation or elimination of hibernation may make the bacteria vulnerable to attack.

references:
Borlongan CV, Hayashi T, Oeltgen PR, Su TP, Wang Y. Hibernation-like state induced by an opioid peptide protects against experimental stroke. BMC Biol. 2009 Jun 17;7:31.

W. Penga, M. L. Cotrinaa, X Hana, H Yua, L. Bekara, L. Bluma, T. Takanoa, G.-F. Tiana, S. A. Goldman and M. Nedergaard. 2009. Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. PNAS 106:12489

Chronic Disease, Cryptic Infections, Hibernation

Suppression of Inflammation and Surviving Cytokine Storms

There are numerous unanswered questions in modern medicine. What is aging, for example? Why do people become more inflamed as they age? What’s with all of the chronic, degenerative diseases? Why is lipid metabolism (LDL, HDL, triglycerides) linked to degenerative diseases, along with immune system function and inflammation? I am only going to start the answers here.

I might as well continue to be cryptic and give you the string of words/concepts I am trying to connect to answer the other questions:
Hydrogen sulfide (H2S), endorphins, hibernation, nuclear receptors (PPARs), antibiotics, chronic inflammatory diseases (fibromyalgia, arthritis, chronic fatigue, Lyme, Morgellon’s, Alzheimer’s, prostatitis, pancreatitis, cancers, etc.), autoimmunity, leaky gut/kidney/brain barrier, autism and H1N1.

First a word of advice: Beware of assuming that molecules are specific, i.e. with unique interactions, and that a small molecule will bind to one and only one protein target. [There are lots of bizarre exceptions to the assumption: Aldolase acts as a structural protein for Toxoplasma motility. Fluorescein is added to make protein fluorescent, but the fluorescein is also transported into cells on its own, i.e. fluorescein and rhodamine labeling can give different results. Heparin binds to most extracellular proteins and it is mostly a hydrophobic interaction -- heparin is not just for clotting anymore.]

Observations from the literature:

• Maternal autoimmunity is linked to autism.
• Autism is linked to leaky gut and chronic inflammation.
• Gut/kidney/brain barriers are based on integrity of extracellular matrix (heparan sulfate) that is compromised by inflammation.
• Chronic diseases require inflammation and circulating inflammatory cytokines (TNF, IL-1, IL-6) are elevated..
• NSAIDs induce leaky gut and release of bacteria toward liver.
• Phagocytosis of bacteria leads to transport of some bacteria, e.g. Chlamydia pneumoniae to other sites of inflammation, e.g. gut to joints.
• Opiods can induce hibernation in rodents.
• Sulfides can induce hibernation in rodents.
• H1N1 my cause lethal pneumonia by lung cytokine storm.
• Inflammatory cytokines and inflammation result from activation of NFkB.
• Hibernation involves PPARs (another nuclear receptor transcription factor).
• Omega-3 fatty acids reduce inflammation via COX-2 prostaglandins, but also by binding to PPARs.
• For most of the diseases under consideration, suppression of inflammation will eliminate symptoms.
• Antibiotics can impact all of these diseases in unpredictable ways. In some cases complete remission can be achieved and in other cases antibiotics can produce lethal cytokine storms.
• Bacterial cell wall components, e.g. lipopolysaccharide, lipid A, are intensely pyrogenic, i.e. inflammatory.

Cryptic Bacteria in our Tissues

The role of bacteria in numerous diseases, including cancers, has been proposed since the early isolation of bacteria from human tissues. Many of these bacteria are difficult to culture and have variable forms viewed by microscope. Because these bacteria are difficult for microbiologists to handle with conventional approaches, their existence and significance has always been questioned. Use of antibiotics to treat chronic, inflammatory conditions has seemed inconsistent with the unproven existence of a bacterial cause. Thus, there is surprise when the inappropriate use of antibiotics leads to a cure.

Cryptic Bacteria Suppress Local Inflammation and Promote Chronic Inflammation

I think that the fundamental problem is the assumption that human tissue is sterile, i.e. free from microorganisms, such as bacteria, unless there is overt infection. Part of the sterile assumption derives from the intense inflammatory response to bacteria. In order for bacteria to survive in tissue, the bacteria must suppress inflammation and the tissue must tolerate the slow leaching of inflammatory bacterial materials.

Chronic Disease Hypothesis

Based on the cryptic bacterial infection hypothesis, many, if not all chronic diseases are initiated by inflammatory events that release bacteria into the blood stream carried in phagocytic cells. The cells migrate and take up residence at a region of inflammation. The bacteria produce molecules that produce tissue hibernation and quell local inflammation in response to the bacteria. The bacteria are, however, a source of ongoing irritation to the tissue and a chronic inflammatory disease results.

Eradication of Cryptic Bacteria

Antibiotics would be a typical choice for killing infecting bacteria. In the case of cryptic, chronic infections, however, application of therapeutic antibiotics may be problematic. The established infections may have produced privileged locations isolated from the vascular system and protected by a bacterial community, e.g. a biofilm. Alternatively, the death of the bacteria and release of pyrogenic factors my produce life-threatening inflammation, that requires careful support.

Hibernation in Rodents Provides Treatment Clues

The compromise of tissue inflammation in response to cryptic bacteria is similar to the physiology of rodent hibernation. In both cases, systemic inflammation is suppressed. At the cellular level, this means that other signaling pathways silence the inflammatory NFkB expression pattern. One of the major nuclear receptors that is activated in hibernation is PPAR. PPAR is activated by opiods and H2S, which also induce hibernation in rodents. There are numerous analogs, inhibitors and H2S donors that could be used to disrupt hibernation (free local suppression of inflammation) or reduce symptoms by suppressing systemic inflammation.

Inflammation Compromises Tissue/Blood Barriers

Inflammation causes a disruption of the integrity of the endothelial extracellular matrix at sites of local inflammation. NFkB activation shuts down the expression of genes involved in heparan sulfate proteoglycan (HSPG) synthesis makes the tissue/blood barrier leaky. Locally this facilitates the recruitment of lymphocytes and neutrophils for defense, but systemically it leads to leaky gut/kidney/brain barriers that permit bacteria to cross.

Convergence of Therapies to Attack Cryptic Infections

The central approaches to attack cryptic infections are a combination of antibiotics and suppression of cytokine storms. These approaches are used in Marshall’s Protocol [http://bacteriality.com/ ], which also exploits a vitamin D receptor antagonist, Olmesartan, that also inhibits NFkB and inflammation.

A similar protocol has been developed by Dr. Michael Powell to inhibit hibernation and attack cryptic infections:
http://www.faqs.org/patents/app/20090163448

These approaches are similar to the lengthy use of antibiotics for the treatment of chronic Lyme disease.

It is very interesting to note that some of the most effective treatments for a long list of degenerative chronic diseases, autoimmune diseases and cancers, use essentially the same protocol that should attack cryptic bacteria and provide support for ensuing inflammation.

Prostate, Prostatitis, Cancer, Causes and Cures

Prostate problems are pervasive, and progressive in the U.S. -- approximately a quarter of a million prostate cancers are diagnosed each year. Chronic inflammation due to age or diet enhances prostatitis and cancer.

Prostate Surrounds Male Urethra

The prostate is a sexual organ. It responds to sexual stimuli, both physical and hormonal, and as a consequence is vulnerable to the same hazards: infection, inflammation, cycles of elaboration and cancer. The prostate straddles the male urethra and inflammatory swelling of the prostrate can strangle the flow of urine from the bladder. The prostate contributes part of the seminal fluid and backward flow of bacteria from the urethra into the prostate can be a source of infection.

Prostate Cells Require Testosterone for Growth

The prostate tissue responds to testosterone. The ebb and flow of testosterone, associated with sexual activity, results in increased production of prostate fluid containing proteins and other components that enhance performance of sperm in the female reproductive tract. The bottom line here is that prostate tissue and derived prostate cancer, responds to testosterone. For this reason, prostate cancer treatment has been based on blocking testosterone stimulation by removal of sources of testosterone and blocking testosterone receptors.

Testosterone Starvation Is Prostate Cancer Treatment

Testosterone, estrogen and vitamin D receptors are all cytoplasmic and the hormone/receptor complexes act as transcription factors to alter nuclear gene expression. It would be expected that prostate cancer, as well as breast, cervical, ovarian, testicular, etc. will respond in a complex manner to steroid hormones, including androgens, estrogens and vitamin D.

Cancer Requires NF-kB Activation

The common biochemistry supporting all cancers is inflammation that is required for proliferation in tissue. Central to inflammation is the transcription factor NF-kB. Inhibitors that block the activation of NF-kB also stop cancer. Most of these blockers are effective against cancer cells grown in culture flasks, because the inhibitors are taken directly into the cells and make contact with NF-kB (or stabilize the NF-kB inhibitor IkB.) Curcumin from turmeric, is one of the most potent inhibitors of NF-kB activation. It is very effective in cultures, but is only modestly effective against inflammation when eaten.

It is difficult to treat secretory tissues, such as prostate, breast, uterus, etc., because much of the tissue is separated from the blood circulation. Thus, infections in these tissues are harder to treat with antibiotics.

Prostatitis Results from Urinary Infections

The prostate is prone to chronic infections. Thus, urinary tract infections (UTIs) can lead to prostate infections (prostatitis). These chronic infections can contribute to chronic systemic inflammation. One symptom of chronic inflammation is depression (treated with SSRIs, antidepressants) another symptom is premature ejaculation (also treated with SSRIs.) Prostatitis-based inflammation can also set the stage for cancer.

Transglutaminase Autoantigen

Autoimmune diseases are also associated with chronic inflammation. One of the common autoantigens in autoimmune disease is tissue transglutaminase (tTG). Celiac is a classic example of the involvement of tTG, since tTG acts on the glutamine amino acids of gluten and converts them into glutamic acid residues. In the process tTG becomes covalently attached to the gluten. The strong heparin binding domains of tTG also facilitate its uptake and processing as an immunogen under inflammatory conditions and result in antibody production to both tTG and gluten. Anti-tTG antibodies and inflammation can also lead to attack on other tissues, such as the thyroid and skin, leading to a variety of celiac-associated autoimmune conditions.

The prostate produces its own transglutaminase. I think it is likely that prostatitis in some cases progresses to an autoimmune disease and prostate transglutaminase is a likely candidate for one of the autoantigens involved. This also predicts an association with celiac and a requirement for chronic systemic infection with a likely elevation of C-reactive protein and inflammatory cytokines (IL-1, IL-6, TNF). Deficiency of vitamin D and omega-3 fatty acids are probably major contributors. Increased risk attributed to consumption of a high fat diet and meat, is probably actually due to inflammation from a high carbohydrate diet and high omega-6 vegetable oils (or perhaps corn-fed meat.)

Protect Prostate with Anti-Inflammatory Diet

Prostate problems are frequently assumed to be a natural result of advancing age, but they are actually symptoms of mismanaged chronic inflammation. Men should not just stand and wait for prostate problems.

Avoidance and treatment of prostate problems seems to be an obvious application for an anti-inflammatory diet and lifestyle.

Extreme Flu Remedies

Experimental Therapies for ARDS, Cytokine Storms

Do not do this at home. There are doctors and hospitals. Use them.

....But, if a doctor emailed me pleading for any ideas that I had to save a bunch of patients suffering from acute respiratory distress syndrome (ARDS) from Tamiflu-resistant H1N1, my first response would be to suggest therapies designed for ARDS from other origins, e.g. burns, septicemia, etc.

Cytokine Storms Are Out of Control
When too much tissue is injured, the local, molecular communication that normally occurs just between cells, spills into the blood stream and becomes potentially lethal. That is what happens in anaphylactic shock. It is also what happens in cytokine storms, where inflammatory cytokines that are normally short-lived and processed locally to progress into recovery, erupt into the blood stream and impact distant organs.

Major disruption of body function by aggressive blood infections or burns over most of the body, will be lethal without heroic medical interventions. These are injuries beyond the evolved adaptations of mammals.  Until recently there were no survivors.

Influenza has been around for a long time. Humans, other mammals and birds get the flu and get over it. Many body cells become infected, antibodies specific to the virus are produced within about a week, the infected cells are killed, the virus is digested and life goes on.

People die from the flu, because an opportunistic pathogen causes a lethal secondary infection, or the body over-reacts and damages itself in attempts to attack its own infected cells. This is a cytokine storm.

Silence the Storms
Cytokine storms can be weathered by blocking the signaling system. Cytokines are just small proteins that are complementary in shape to corresponding protein receptors that penetrate through the surface membranes of cells throughout the body. Binding of cytokine to receptor changes the shape of the receptor and transmits a signal into the cytoplasm of the receptive cell. This turns on aggressive behavior of immune cells and triggers more inflammatory signaling in other cells. This causes fever, malaise, etc.

...But, I was the one the doctor is pleading with to save the people. And I know that there is more to cytokine signaling than just cytokines and receptors. There are also heparan sulfate proteoglycans (HSPGs). Cytokines are not supposed to be broadcast throughout the body. Cytokines function in the space between cells, the extracellular matrix. Polysaccharides attached to membrane proteins, HSPGs, are secreted at one end of the cells, sweep across the surface and are taken back up at the other end. Cytokines have heparan-binding domains and so they stick to the heparan and are swept along. Cytokines can move from one cell to another as the sweeping HSPGs of adjacent cells come in contact.

HSPGs Mediate Cytokine Signaling
The critical point here is that cytokines bind to their receptors with the heparan between -- the cytokine and receptor are like two halves of a bun and the hot dog is the heparan. In fact the heparan bridges two cytokine/receptor complexes to make an active, signaling pentamer.

Heparin Can Block Cytokine Signaling
Heparin is a fragment of heparan sulfate produced by enzymatic degradation of HSPG. Commercial heparin, used to block blood clotting, is obtained from the mast cells of lungs and intestines of hogs and cattle. The mast cells release heparin and histamine in response to parasites or pollen. Since heparin is a short version of heparan sulfate, it can block the formation of active cytokine/receptor complexes.

Heparin is used in a mist to treat the lungs of burn patients. It is also injected into some infertility patients to suppress inflammation that is inhibiting implantation and gestation. It is also effective in treatment of autoimmune inflammation in Crohn’s disease. I think it should be tested as a therapy for H1N1 cytokine storms. It may be useful in nebulizing mists and oral treatment of intestines.

Berberine Binds to HSPG
Berberine is a phytochemical from Barberry traditionally used in the treatment of intestinal infections and arthritis. It also binds to heparan sulfate to form fluorescent complexes visible in microscopy. Berberine-treated mast cells glow brightly. Heparan sulfate can also be detected in Alzheimer’s plaque, atherosclerotic plaque and prion complexes. Because berberine binds to heparan sulfate, it should also disrupt cytokine signaling. It has been used successfully in treatment of septicemic ARDS.

Curcumin Blocks NFkB
One of the most potent chemicals that blocks inflammatory signaling via the inflammatory transcription factor, NFkB, is curcumin. Curcumin is a major component of the spice turmeric. Oral curcumin can be enhanced by co-administration of black pepper, because the piperine in pepper inhibits intestinal inactivation.

Anti-Inflammatory Diet
Of course, I would also recommend vigorous implementation of an anti-inflammatory diet and lifestyle to support any medical treatment.

Allergy, Asthma, Autoimmunity Start the Same Way

Inflammation is the current medical buzzword. Name the disease and inflammation is there.

Reproduction Requires Controlled Inflammation
Aspirin blocks many of the steps in triggering inflammation and thus, aspirin administration can be used to reveal a role of inflammation in many unexpected places. Aspirin is effective in blocking some forms of infertility, inhibiting miscarriages and ameliorating postpartum depression. So inflammation is a critical part of reproduction. But, also notice that depression is a symptom of chronic inflammation.

Cancer Requires Inflammation
High dose (IV) aspirin has been successfully used to treat cancer. Inflammation is required for cancer growth, because both use the same transcription factor, NFkB. The aberrant signaling of cancer cells would normally lead to programed cell death, apoptosis, but inflammation blocks apoptosis. Aspirin can in turn block NFkB and in the absence of inflammation, cancer cells die by apoptosis.

Inflammation is Self-Limiting
Aspirin also transforms the COX/lipoxidase system to produce anti-inflammatory prostaglandins/eicosinoids. Inflammation normally progresses into anti-inflammation. Blocking this progression leads to chronic inflammation and a shift from local to systemic inflammation with the rise of inflammatory interleukins in the blood stream.

Immune Response Requires Inflammation
The signal molecules (IL-1, IL-6, TNF) and transcription factor, NFkB, associated with inflammation were all initially identified in the development of lymphocytes. Hence, IL stands for interleukin, a hormone that triggers leukocyte (literally white blood cells or cells associated with the lymphatic immune system, i.e. lymphocytes) development. The nuclear factor, i.e. transcription factor, involved in expression of the large chain, kappa, of immunoglobulins in B cells, was called NFkB.

Genes Expressed by NFkB Cause Symptoms of Inflammation
About five dozen genes are under control of NFkB. Among these are COX-2, the enzyme that converts omega-6 arachidonic acid to inflammatory prostaglandins; iNOS, the enzyme that produces nitric oxide that dilates blood vessels to produce hot, red skin; and the inflammatory interleukins, IL-1, IL-6 and TNF, associated with autoimmune disease, fatigue and cachexia (wasting).

Autoimmunity and Allergy Start with Inflammation
Medical treatments focus on symptom abatement and ignore cause. What causes obesity, allergy or autoimmune disease? The answer appears to be chronic systemic inflammation plus exposure to unusual proteins. The unusual proteins are immunogenic, i.e. interact with the immune system to produce antibodies or reactive T-cell receptors, and are subsequently recognized as autoantigens or allergens, that are the targets for immune attack. Inspection of these autoantigens and allergens shows that they all have one thing in common, they bind to heparin via a strong heparin-binding protein domain that is typically a triplet of adjacent basic amino acids.

Heparin is a Short, Highly Sulfated Fragment of Heparan Sulfate
Commercial heparin is purified from the intestines of hogs and cattle. Heparin is released from mast cells (made fluorescent for microscopy using berberine) along with histamine and is released into the intestines to block pathogens from binding to the heparan sulfate that is part of the intestine surface. The heparin is anti-inflammatory and it contributes to minimizing the inflammatory response of the intestines to food.

Inflammation Reduces Heparan Sulfate Production
Pathogen-generated inflammation of the intestines reduces heparan sulfate production and increases immune response to food antigens. NFkB activation by inflammation turns off the production of some genes needed for heparan sulfate proteoglycan (HSPG) synthesis. Since HSPG is a major component of the basement membrane that holds tissues together, the reduction of HSPG results in protein loss (proteinuria) from kidneys, leaking of intestines, and disruption of the blood/brain barrier.

Reduction of HSPG Results in Immunological Presentation of Autoantigens/Allergens
Proteins are brought into cells by specific binding to protein receptors. In many cases, particularly involving signaling or growth factors, both the signal molecules and the receptors bind to heparin. In addition, there is a robust circulation of HSPG, which is secreted and internalized with a half-life of approximately six hours. The sweep of the HSPGs take heparin-binding proteins with them for internalization, e.g. HIV-TAT, heparanase, tissue transglutaminase. I think that this HSPG sweep under inflammatory conditions also internalizes basic autoantigens and allergens with strong heparin-binding domains. This internalization is the first step toward immunological presentation and the immune response to autoantigens and allergens.

Autoantigen/autoantibody/HSPG Complexes Kill Cells
Antibodies against self-antigens, autoantigens form antigen/antibody complexes that also bind to and cross-link HSPGs, because of the heparin-binding domains of the autoantigens. The large complexes may disrupt HSPG circulation and trigger apoptosis or abnormal physiology. There are many other examples of heparin-based complexes that are toxic, e.g. Alzheimer’s amyloid plaque, diabetic beta cell antibody complexes, celiac gluten/tRG antibody complexes, multiple sclerosis myelin antibody complexes, atherosclerotic plaque.

Anti-Inflammatory Diet and Lifestyle Protects
Dietary and lifestyle adjustments that minimize inflammation, e.g. low starch, no HFCS, low vegetable oil (except olive) and supplements of vitamins D & C, fish oil (omega-3) and glucosamine, reduce the risk of allergies/asthma, degenerative diseases and cancers. Simple, high level supplements with fish oil reduce numerous mental disorders, e.g. depression, ADHD; infertility, pre-eclampsia and postpartum depression; allergies, asthma; arthritis, atherosclerosis; burn recovery, septicemia and head injury.

Reducing Inflammation is a Panacea for Modern Diseases
Most modern diseases have an inflammatory component, because modern diets are rich in inflammatory components, e.g. starch/sugar, corn/soy oil, HFCS, trans fats, and exercise is minimal. The medical industry has not successfully promoted healthy eating and exercise; and in fact has promoted the devastating replacement of saturated fats with inflammatory polyunsaturated vegetable oils. Meat production has moved away from grazing on omega-3-rich plant vegetation to omega-6-rich corn and soy. Replacement of the corn/soy based agricultural economy would have predictably immense beneficial impact in reducing inflammation-based degenerative autoimmune diseases and cancers.

Where’s the Aspirin?

Aspirin is the traditional anti-inflammatory agent. Many of us grew up with the quintessential doctoring phrase, “Take two aspirin and call me in the morning.” Aspirin stops inflammation in several ways. Like all drugs, it interacts with many different proteins/enzymes. In fact it interacts so intimately with the inflammatory system that it suggests that the process of inflammation may require an aspirin-like molecule to function normally.

Aspirin Binds to Multiple Enzymes of Inflammation

Aspirin is observed to reduce inflammation. That means that ingested aspirin tablet dissolve in the stomach and pass through the intestines into the blood stream and subsequently bath cells of the blood and the endothelium that lines the blood vessels. In order to reach the blood stream, the aspirin must pass through the intestinal cells. That passage requires binding to a protein transport molecule.

Cells responding to an inflammatory signal (NFkB, transcription factor is activated) synthesize enzymes that release unsaturated fatty acids (ARA, EPA, DHA) from membrane phospholipids (PLA2, phospholipase A2), form a cyclic epoxide from the fatty acid (prostaglandin H2 synthase 2, also called cyclooxygenase 2, COX-2).

Aspirin binds to the inhibitor that normally inactivates NFkB and prevents NFkB activation that is required for inflammation. Aspirin also binds to PLA2 and prevents fatty acid release and thereby blocks activation of inflammation. Aspirin also binds to COX-2 and blocks the production of inflammatory prostaglandins from ARA. But that is not all that aspirin does.

Inflammation Resolution Uses Aspirin-COX-2 Interaction

The strange interaction that makes aspirin suspicious is that aspirin doesn’t just interfere with the action of enzymes, it subtly changes their specificity. Thus aspirin chemically transfers its acetyl group (CH3-COOH-) to an amino acid in the active site of COX-2 to produce a new group of anti-inflammatory lipoxins from ARA, EPA and DHA.

This raises the question of whether aspirin is a natural dietary modulator of inflammation. Recall that aspirin was initially obtained from willow (Salix) bark. Unfortunately, the data are conflicting. Initial research indicated that grains (naturally inflammatory) lacked aspirin, but many herbs, spices and leafy vegetables (naturally anti-inflammatory) contained aspirin. Subsequent tests refuted this work. It would be consistent with observations that some dietary components are anti-inflammatory, but candidate acetyl donors have not been identified.

Speculative acetyl candidates may include the menthol relatives, such as menthyl acetate (figure). Peppermint oil, which contains mostly menthol with some menthyl acetate, is more effective in the treatment of inflammatory bowel disease than most pharmaceuticals prescribed to treat the condition. This anti-inflammatory activity may be due in part to the aspirin-like chemical structure and function of the menthyl acetate. Also note that acetic acid/vinegar is sometimes suggested as a cure-all. This activity may be a consequence of its formation of ester linkages with alcohols that have structures similar to menthol.

Large Dose Aspirin as Cancer Treatment

The potent anti-inflammatory effects of aspirin have been compromised, because inflammation is an essential developmental activity. Thus, the integrity of the gut, for example, requires modest production of inflammatory prostaglandins and a pill of aspirin can disrupt gut tissue. Large doses of aspirin cannot be given orally. Intravenous administration of large doses of aspirin, however, is possible and the impact on process that require inflammation is dramatic.

Anecdotal evidence indicates that large dose aspirin is able to disrupt cancers, because proliferation of cancer cells requires NFkB activation and other inflammatory responses. High doses of aspirin also cause other potentially dangerous complications, such as short-circuiting oxidative phosphorylation of mitochondria and increasing nitric oxide free radical production. Still, the impact of high dose aspirin on some diseases is so amazing that it is being actively and carefully pursued.