3-Neuroimmune Mechanisms of the Subluxation Complex

Subluxation is spoken here!

Article 26: THE CHIROPRACTIC DEFINITION OF SUBLUXATION A subluxation is the condition of a vertebra that has lost its proper juxtaposition with the one above or the one below, or both; to an extent less than a luxation; which impinges nerves and interferes with the transmission of mental impulses.

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#2: This produces an “inflammatory soup” that spreads from the involved connective tissue matrix to the local neurovascular tissues. #3: Neuronal inflammation produces end-organ changes attributable to 1) neurogenic inflammation of the sensory-effector system; and 2) sympathetic lymph node denervation. #1: Articular distortion places a mechanical stress on the periarticular soft tissues. This takes the form of altered stresses carried by the connective tissue matrix. #4: Inflammatory mediators escape the connective tissue matrix and pass into the vascular compartment to produce global neuroendocrine alterations and systemic physiological changes. Subluxation

5 Emergent Phenomena of Subluxation Inflammation EP 1: Mechanical Distortion Matrix & Cellular Components EP 2: Biochemical Transduction
AA
PGE2
LTB4
TXA2
EP 3: Action Potential Facilitation Inflammogens have been shown to lower the threshold of action potential. EP 4: Immune Infiltration Immune infiltration magnifies and concentrates the "inflammatory soup" which exacerbates the affects. EP 5: Cytokine Production Cytokine infiltrate is known to provoke gene expression and profound tissue alterations. Subluxation results in a piezoelectric effect which waves across the entire mass of interconnected connective tissues.

Emergence of Mechanical Distortion to Connective Tissue Matrix Components #1: Connective tissue distortion alters the mechanical load borne by the fibrous matrix with loss of normal tension integrity. #2: Fluid dynamic changes as a result of pressure gradient changes alter nutrient flow and waste removal throughout the distorted connective tissue. #3: Altered dipole distances between matrix fiber-salt complexes triggers a piezoelectric effect which moves throughout the entire connective tissue system. #4: These and other matrix alterations often activate matrix remodeling mechanisms such as the Matrix Metalloproteinase system.

Defining Cellular Components Fibrobloasts Macrophages Mast Cells Gartner and Hiatt. Color Atlas of Histology 5 th ed. pp. 51-56

Connective Tissue: Noncellular Components Fibrous Matrix
Collagen Fibers
Elastin Fibers
Reticular Fibers
Gartner and Hiatt. Color Atlas of Histology 5 th ed. pp. 51-56 Amorphous Ground Substance
Glycosaminoglycans
Proteoglycans
Glycoproteins: Fibronectin
Extracellular Fluid

Proteoglycan Aggregate Many of the proteoglycan molecules are linked to hyaluronic acid, forming massive molecules , such as aggrecans aggregate, of enormous electrochemical domains that attract osmotically active cations (e.g., Na+), forming hydrated molecules that provide a gel-like consistency. Gartner and Hiatt. Color Atlas of Histology 5 th ed. pp. 51-56

Connective Tissue Filtration Distorted extracellular matrix tissues experience an alteration in fluid dynamics . The connective tissue can trap toxins , cellular metabolites and inflammatory by-products. Gartner and Hiatt. Color Atlas of Histology 5 th ed. pp. 51-56

Piezoelectric Effect The nature of the piezoelectric effect is closely related to the occurrence of electric dipole moments in solids. Of decisive importance for the piezoelectric effect is the change of polarization when applying a mechanical stress. http://en.wikipedia.org/wiki/Piezoelectricity

Piezoelectricity of Collagen Collagen exhibits the polar uniaxial orientation of molecular dipoles in its structure. Potentials are thought to occur when a number of collagen molecules are stressed in the same way displacing significant numbers of the charge carriers from the inside to the surface of the specimen. http://en.wikipedia.org/wiki/Piezoelectricity

Liquid Crystal Matrix Connective tissue fibers are arranged in highly regular arrays . These arrays of connective tissue fibers are associated with “ enormous electrochemical domains .” The name for a highly regular array of charge bearing molecules is a crystal regardless if it is solid or liquid. Church. The Genie in Your Genes. p. 146.

Matrix as Semiconductor The crystalline structure resulting from collagen molecules, GAGs and an assortment of ions produces an organic or biological semiconductor . A semiconductor is a material that has an electrical conductivity between that of a conductor and an insulator . http://en.wikipedia.org/wiki/Semiconductor

Semiconductor Physiology The semiconductor nature of biological tissues mirror those of other semiconductor materials. These include:
To conduct and store energy
To conduct and filter information
To amplify and attenuate signals
In a sense, the connective tissue matrix is an information processor .
It connects the extracellular matrix to the nuclear matrix electrostatically as well as mechanically .

Semiconductor Pathophysiology A damaged or otherwise debris filled or intoxicated matrix will alter normal semiconductor physiology. Electrochemical signal bias is introduced that has the potential to disrupt cellular, subcellular and genomic components. The results include a variety of neuro-endocrine-immune effects.

Damage to ECM Molecules Valence interplay and damage from attempts at enzymatic “cleaning” can alter the normal anatomical and physiological properties of the ECM.

Fibroblast Response Fibroblasts respond to damage or inflammation in the ECM with the release of Matrix Metalloproteinases . These are secreted in an inactive form. They are activated by a variety of ROS.

Matrix Metalloproteinases MMP come in a wide variety of isoforms and are designed to breakdown damaged and aging matrix proteins. This process has a high mineral co-factor demand such as zinc.

Macrophage Response Macrophages respond to inflammatory changes with the release of Reactive Oxygen Species such as:
Superoxides
Singlet oxygens
Peroxides

Reactive Oxygen Species ROS are various caustic agents that have a broad, non-specific destructive effect . This process has a high mineral co-factor demand such as zinc, copper, magnesium and manganese.

Types of Antioxidant Protection Intracellular versus Extracellular Endogenous versus Exogenous

Extracellular Free Radical Protection Uric acid Melatonin Ceruloplasmin Spare Parts Iron Sequestration

Uric Acid as Antioxidant Uric acid (UA) is an oxypurine produced from xanthine by the enzyme xanthine oxidase , and is an intermediate product of purine metabolism. Clinical and Experimental Nephrology 9 (3): 195–205. When compared to other antioxidants , UA has the highest concentration of any in the blood and provides about half of the total antioxidant capacity of human serum . Free Radical Biology and Medicine 14 (6): 615–31.
Self W T , Stadtman T C PNAS 2000;97:7208-7213

Could Something More Intelligent be at Work? The higher serum uric acid concentration seemed associated with elevated total serum antioxidant capacity among individuals with atherosclerosis. This finding is consistent with experimental evidence suggesting that hyperuricemia may be a compensatory mechanism to counteract oxidative damage related to atherosclerosis and aging in humans. Atherosclerosis. 2000 Jan;148(1):131-9

Melatonin as Antioxidant Melatonin is a powerful antioxidant and, unlike conventional antioxidants such as vitamins C and E and glutathione, it is both produced in the human body and is acquired in the diet (fruits, vegetables, cereals and herbs etc., contain melatonin). Journal of Pineal Research 42 (1): 28–42. Melatonin easily crosses cell membranes and the blood-brain barrier. Critical Reviews in Biochemistry and Molecular Biology 44 (4): 175–200. Unlike other antioxidants, melatonin does not undergo redox cycling .

Dr. Bonci, Please! Get to the POINT!

Carpe Lucem

AA
PGE2
LTB4
TXA2

Emergence of Mechanical Distortion to Cell Membrane Components #1: Cell membrane distortion activates the Ca2+ enzyme PLA2 which liberates Arachidonic Acid (AA) from the phospholipid bilayer. #2: The proinflammatory AA is then transformed into a variety of (series 2) inflammatory eicosanoids. #3: Cyclooygenase (COX) transforms AA into prostaglandin E2 (PGE2). #4: 5-Lipoxygenase (5-LO) transforms AA into Leukotriene B4 (LTB4). #5: Thromboxane Synthase (TBXA) transforms AA into TXA2.

Emergence of Mechanical Distortion to Tissue Mast Cell Components #1: Cellular damage and distortion of tissue resident mast cells results in the release of stored vesicle compounds and other intracellular electrolytes. #2: Potassium [K+] moves to the extracellular compartments where it serves as a powerful algogen. #3: Histamine acts as a powerful vasodilator. #4: Heparin acts as a powerful anticoagulant. #5: Proteinases act to restructure matrix components to facilitate removal and repair of damaged structures #6: Cytokine release to augment the immune cell populations.

AA
PGE2
LTB4
TXA2

Emergence of Action Potential Facilitation Series-2 Eicosanoids effect the following transformation of neuronal fibers:
Organizes/Concentrates Sodium Channels
Demyelination of Axonal Fibers
Enhances the Release of Substance-P
Cytokines such as Interleukin-1 enhances the production of Series-2 Eicosanoids as well as Tachykinin production such as Substance-P. COX/PGE2 PLA2/AA Cytokines

Demyelination
“In this experiment, demyelination , including breakdown of myelin sheath, intracellular vacuolization (IC edema), and decreased extracellular space, was found in the PLA2-exposed nerve root 3 days after injection of PLA2.” Chen C, et al. Effects of phospholipase A2 on lumbar nerve root structure and function. Spine 1997; 2(10): 1057-1064.

Sodium Channel Restructuring
“ It was repo rted that demyelination is associated with a reorganization of the macromolecular structure of the axonal membrane and a redistribution of sodium ion channels along the demyelinated axolemma. ” Chen C, et al. Effects of phospholipase A2 on lumbar nerve root structure and function. Spine 1997; 2(10): 1057-1064.

Immunochemicals Sensitize Nociceptors “[T]he present experiments have demonstrated, for the first time, that prostaglandins indeed act directly to sensitize nociceptors .” Pitchford S., Levine JD. Prostaglandins sensitize nociceptors in cell culture. Neuroscience letters 1991; 132:105-108.

AA
PGE2
LTB4
TXA2

SP binds to NK-1 receptors on the tissue mast cell with the release of histamine. Histamine provokes vasodilation. Redness, edema and extravasation of immune cells emerges from the vasodilation. Emergent Immune Infiltration of Connective Tissue SP

Granulocyte Infiltration is Mast Cell Dependent The effects of substance-P on tissue swelling, vascular permeability, and granulocyte infiltration were virtually entirely mast cell dependent . J Clin Invest. 1989 October; 84(4): 1276–1286.

AA
PGE2
LTB4
TXA2

Cytokine Production and Emergent Connective Tissue Changes IL-1 IL-6 TNF-a AA LTB4 TXA2 MMP ROS Chemotatic Factors “ Inflammatory Soup” SP Lymphocytes Macrophages Neutrophils

Tissue Injury
Toxic Oxygen Metabolites
Proteases
Neurtophil Chemotactic Factors
CoagulationFactors
Arachidonic Acid Metabolites
Nitric Oxide
Fibrosis
Growth Factors (PDGF, FGF, TGF-B)
Fibrogenic Cytokines
Angiogenesis Factors (FGF)
"Remodeling" Collagenases
Mechanisms of End-Organ Transformation http://www.robbinspathology.com/ SP

Sickness Behaviors and the Chiropractic Adjustment Pyrexia Anorexia Somnolence Cytokines released from SI Joint with Chiropractic Adjustment provokes the 3 classic sick behaviors

Sickness Behaviors Proinflammatory cytokines acting in the brain cause sickness behaviors . Brain Behav Immun. 2003 Feb;17 Suppl 1:S112-8.

Dr. Bonci, Please! Get to the POINT!

Carpe Lucem

Emergence of the Inflammatory-Facilitating Lesion Sensory-Effector Response: Antidromic release of tachykinins through nociceptor afferents drives Neurogenic Inflammation and en-organ transformation and dis-ease. Motor Response: Lowered threshold on somatic and autonomic motor nerves facilitates somatic muscle spasms, sympathetic and parasympathetic efferent responses, end-organ changes and dis-ease. Series-2 Eicosanoids Cytokines

Lymph Node Denervation

Autonomic innervation and regulation of the immune system (1987-2007). Brain Behav Immun. 2007 Aug;21(6):736-45.

Lymph Node Innervation Dense varicose plexuses enter the nodes with the vasculature in the hilar region and continued with the vasculature into the medullary region . Fine, delicate varicosities and small vascular plexuses continue into the cortical and paracortical regions surrounding the germinal centers; some varicosities ended among lymphocytes . A subcapsular plexus contributed fibers into the cortical and paracortical regions. Brain Res Bull. 1984 Dec;13(6):693-9.

Noradrenergic sympathetic innervation of the spleen: I. Nerve fibers associate with lymphocytes and macrophages in specific compartments of the splenic white pulp. J Neurosci Res. 1987;18(1):28-36, 118-21.

Neuroimmune Competency These findings suggest that noradrenergic fibers innervate both the vasculature and parenchymal regions of lymph nodes, and may participate in the modulation of immune responses in these organs. Brain Res Bull. 1984 Dec;13(6):693-9.

5 Emergent Phenomena of Lymph Node Denervation EP 1: Action Potential Facilitation EP 2: Norepinephrine Hypercycling EP 3: Monoamine Oxidation EP 4: Neuronal Free-Radical Formation EP 5: Lymph Node Denervation ROS

Axon Varicosity & NE Cycling

Monoamine Oxidase Monoamine oxidases catalyze the oxidative deamination of monoamines. Oxygen is used to remove an amine group from a molecule, resulting in the corresponding aldehyde and ammonia. Chemical Rxns:
Epinephrine or norepinephrine to 3,4-Dihydroxymandelic acid
Metanephrine or normetanephrine to vanillylmandelic acid (VMA)

Reactive oxygen species production by monoamine oxidases damage cells. Altogether, these findings show that, in a normal cell environment, MAO can be a source of reactive oxygen species which could have a functional impact on cell functions . Naunyn Schmiedebergs Arch Pharmacol. 1999 May;359(5):428-31.

Superoxide Dismutase SODs are enzymes that catalyze the breakdown of the superoxide anion into oxygen and hydrogen peroxide . Free Radic Biol Med. 2002 Aug 1;33(3):337-49. CRC Crit Rev Biochem. 1987;22(2):111-80. SOD enzymes are present in almost all aerobic cells and in extracellular fluids. Mol Aspects Med. 2005 Aug-Oct;26(4-5):340-52.

Superoxide Dismutase Superoxide dismutase enzymes contain metal ion cofactors that can be copper, zinc, manganese or iron . In humans, the copper/zinc SOD is present in the cytosol, while manganese SOD is present in the mitochondrion. CRC Crit Rev Biochem. 1987;22(2):111-80. There also exists a third form of SOD in extracellular fluids , which contains copper and zinc in its active sites. Int J Biochem Cell Biol. 2005 Dec;37(12):2466-71.

Catalase Catalases are enzymes that catalyse the conversion of hydrogen peroxide to water and oxygen , using either an iron or manganese cofactor. Cell Mol Life Sci 61 (2): 192–208. Prog Biophys Mol Biol 72 (1): 19–66. This protein is localized to peroxisomes in most eukaryotic cells. Free Radic Biol Med 13 (5): 557–80.

Glutathione Peroxidase Glutathione peroxidase is an enzyme containing four selenium-cofactors that catalyzes the breakdown of hydrogen peroxide and organic hydroperoxides. Free Radic Biol Med 27 (9–10): 951–65.

Consequences of NE/ROS The toxic effects of NE on the sympathetic nerve terminals are mediated via the formation of NE-derived oxygen free radicals . Preservation of the neuronal NE reuptake mechanism is functionally important … Circulation. 2000 Jul 4;102(1):96-103.

Lymph Node Denervation: Immune Consequences APCs Antigen Presenting Cells such as macrophages and Langerhan's cells become accentuated. This can lead to magnified antigen harvesting. T-Cells T-Lymphocyte activity becomes depressed. This may lead to disorders such as atopic dermatitis as well as fungal and viral infections. Natural Killer activity and other cell mediated immune function is impaired. B-Cells B-Lymphocyte activity is accentuated. There is an enhanced release of learned antibody response which includes autoantibodies. MAO Generated ROS Lymph Node Denervation

Peripheral Lymph Tissue Innervation Taken together these results demonstrate that the peripheral sympathetic nervous system influences the migration and accumulation in vivo of both naive and memory/effector lymphocytes in mucosal lymphoid tissues. Gonzalez-Ariki S. The role of sympathetic innervation of the gut in regulating mucosal immune responses. Brain Behav Immun. 1998 Mar;12(1):53-63.

Loss of Noradrenergic Stimuli These results demonstrate that depletion of NA [noradrenergic] innervation alters cellular proliferation and lymphocyte migration in primary and secondary lymphoid organs. Madden KS. Sympathetic nervous system modulation of the immune system. II. Induction of lymphocyte proliferation and migration in vivo by chemical sympathectomy. J Neuroimmunol. 1994 Jan;49(1-2):67-75.

Lymph Node Denervation Thus, sympathetic denervation appears to impair T cell activity in vivo and in vitro. Overall, these results indicate the SNS plays a role in generation of cell-mediated immunity. Madden KS. Sympathetic neural modulation of the immune system. I. Depression of T cell immunity in vivo and vitro following chemical sympathectomy. Brain Behav Immun. 1989 Mar;3(1):72-89.

Chiropractic Physiology In considering physiology from a Chiropractic standpoint , there is much that may be said; more than is given in any other text book on physiology. This [is] because Chiropractic deals with “life” that has not been dealt with by scientists of the past or any other scientific teaching of the present. HARRY E. VEDDER, D. C., Ph. C. A TEXT BOOK ON CHIROPRACTIC PHYSIOLOGY FIFTH EDITION COPYRIGHT, 1922

“ Believe nothing. No matter where you read it, or who said it, even if I have said it, unless it agrees with your own reason and your own common sense.” Siddhartha Gautama The Buddha

Art. 19: THE THREE PHASES OF CHIROPRACTIC STUDY 1. Study of the Immaterial. 2. Study of the Material. 3. Study of Art. Stephenson RW. Chiropractic Text Book. Freshman Text. 1927.

Study of Art The study of Art is learning how to do the things that every chiropractor must do, scientifically and skillfully; such as, analysis, palpation and adjusting. All of these require skill as well as mental work . Stephenson RW. Chiropractic Text Book Freshman Text. 1927.

The Chiropractic Adjustment: The Best Prevention Primary Prevention: Concerned with preventing the development of disease in a susceptible or potentially susceptible population. Adjusting subluxations prevents the development of dis-ease. Secondary Prevention: Involves early diagnosis and prompt therapy to shorten the duration of illness, its severity and limit its sequelae. Detecting and adjusting subluxations removes a potent risk factor for dis-ease. Tertiary Prevention: Is important in limiting the degree of disability and promoting rehabilitation in chronic and irreversible dis-ease. Adjusting subluxations help to prevent progressive disabilities. Risk Factor: In epidemiology, a risk factor is a variable associated with an increased risk of disease or infection. Risk factors or determinants are correlational and not necessarily causal, because correlation does not imply causation.

Subluxation: A Modifiable Dis-Ease Risk Factor Risk Factor Defined: Factors in the environment, or chemical , psychological, or physiological, that are thought to predispose an individual to the development of a disease. Since subluxation predisposes an individual to dis-ease, then it can be thought of as a risk factor for dis-ease. Removing the subluxation through chiropractic adjustments reduces the potential for dis-ease. This occurs when inflammatory fluids produced by mechanical distortion are "flushed" out of the intervertebral foramen thus reducing neurogenic inflammation and removing the forces driving lymph node denervation. Therefore, adjusting subluxation and normalizing function reduces the potential for dis-ease. Neurogenic Inflammation: Causes infiltration that drives end-organ transformation through macrophage activation. Sympathetic-Lymph Node Denervation: Causes immune dysregulation with systems wide influences.

3-Neuroimmune Mechanisms of the Subluxation Complex

by Andrew Bonci on Nov 30, 2011

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3-Neuroimmune Mechanisms of the Subluxation Complex — Presentation Transcript