MCS ad Etiology: Naturally Sensitive

[michael edward badolato jr]

MCS people are naturally sensitive - in a descriptive portrait attitude and functional typology - genetically introverted intuitive; counterweight to the rarified air of intuition - an extraordinary dependence on sense impressions - and the development of hypersensitivity of the sense organs (Jung 1921).

MCS can be expected to be a relatively broad set of genetic differences - a natural genetic combination rather than a defect.

Research reported by Veronesi 2001, 2000, Roy 2000  (MCS 15) confirm that mice intolerant of pollution have quantitative differences in receptors and pathways - they are more sensitive.

 

VERONESI B. AND OORTGIESEN M. NEUROGENIC INFLAMMATION AND PARTICULATE MATTER AIR POLLUTANTS. NEUROTOX 22;795-810 2001: 

"...taken together, the above in vivo and in vitro studies suggested that the variable inflammatory sensitivity to PM observed in different mouse strains (ie Balb/C, B6) related to quantitative differences in the neuropeptide, VR1 receptors and acid sensitive pathways found on sensory neurons that innervate the nasal and upper pulmonary airway. Such data showed how genetically determined differences in sensory neural pathways could influence expressions of PM-induced airway inflammation...genetic differences are thought to underlie these variations and have been experimentally demonstrated for ozone (Kleeberger 1995, Zhang 1995), nitrogen dioxide (Holroyd 1997), and diesel exhaust (Ichinose 1997, Miyabara 1998)..."

 

Because of genetic disposition and environmental exposure - especially a continuous aerosol of combustion byproducts - defects develop in the airway epithelium exposing the nerves.

 

MEGGS W.J. HYPOTHESIS FOR INDUCTION AND PROPAGATION OF CHEMICAL SENSITIVITY BASED ON BIOPSY STUDIES. ENVIRON HEALTH PERSPECT 1997 (SUPPL 2) 473-78:

....There are defects in the tight junctions between respiratory epithelial cells, focal desquamation of the epithelial cells in places, hypertrophy of glandular structures, lymphocytic infiltrates, and proliferation of sensory nerve fibers...tumor necrosis factor is produced by lymphocytes....

MEGGS W.J. ARCH ENV HEALTH 1999 54(5) 309-11:

....The mechanism by which inflammatory conditions are provoked by chemicals is via chemoreceptors on sensory nerve C-fibers with the release of substance P and other mediators of neurogenic inflammation...progression of inflammation to organ damage is possible to those who continue to be exposed...

Bellina Veronesi and Marga Oortgiesen. National Health Effects and Research Laboratory, Cellular and Molecular Branch, Neurotoxicology Division, US Environmental Protection Agency, Research Triangle Park, North Carolina. Cato Research LTD., Durham, North Carolina.

VERONESI B. & OORTGIESEN M. NEUROGENIC INFLAMMATION AND PARTICULATE MATTER (PM) AIR POLLUTANTS. NEUROTOXICOLOGY 2001 (22):795-810:

.....neurogenic inflammation. In this process, a cascade of cellular and sub-cellular events...the sensory nervous system and its peptidenergic transmitters (i.e. SP, CGRP, NKA) initiate and sustain this inflammation...

...Once released these pro-inflammatory peptides interact with a variety of immune (e.g. lymphocytes, neutrophils, macrophages, eosinophils) and non immune (e.g. smooth muscle, endothelial cells of the vasculature, epithelial cells that line the lumen of the airways and gut, keratinocytes of the skin) target cells...overt symptoms of inflammation (e.g. erythema, edema, vasodilitation, vasoconstriction, mucous secretion) through the phenomenon of the axon reflex... on involvement of the immune system, the initial symptoms of inflammation are exacerbated and perpetuated with resulting tissue damage...

...In normal physiological settings, the respiratory epithelial population and its sensory innervation act reciprocally to influence the growth, differentiation, and homeostasis of each other...These relationships are especially critical to the organism's inflammatory response...In all instances, sensory neurons release 10-200 fold higher levels of IL-6 (pro-inflammatory cytokine) relative to epithelial cells...

...conditions associated with chemical pollutants are characterized by damage to the epithelial barrier that lines the airways...

... Such damage not only results in the loss of critical neuropeptide deactivating enzymes (e.g. NEP) but allows the sensory fiber to physically extend closer to the airway lumen and in closer proximity to the inhaled PM particles...enhanced and prolonged inflammatory events...increased inflammatory response...

 

Given damage to the airway epithelium, multiplied nerves, and genetic propensity one would expect elevated inflammatory markers in MCS people.

KIMATA, H. EFFECT OF EXPOSURE TO VOLATILE ORGANIC COMPOUNDS ON PLASMA LEVELS OF NEUROPEPTIDES, NERVE GROWTH FACTOR, AND HISTAMINE IN PATIENTS WITH SELF REPORTED MULTIPLE CHEMICAL SENSITIVITY. INT JRNL OF HYG AND ENV H 207;2:159-63 2004.

Elevated levels indicate a wide ranging inflammation - including many other inflammatory substances.

25 normal, MCS, and allergy subjects (total 75) before and after exposure to a painted room.

Substance P (SP), Vasoactive Intestinal Peptide (VIP), Nerve Growth Factor (NGF), and Histamine (H).

For SP Normal 38 before 39 after. MCS 105 before 153 after. Allergy 75 before 74 after.
For VIP Normal 10 before 11 after. MCS 43 before 68 after. Allergy 22 before 21 after.
For NGF Normal 148 before 156 after. MCS 1129 before 1696 after. Allergy 550 before 560 after.
For H Normal 260 before 260 after. MCS 271 before 534 after. Allergy 550 before 560 after.

The normal and allergy group are nearly unchanged after exposure to paint (VOC).

MCS people have elevated markers even before exposure to paint which can be attributed to the defective airway epithelium and ambient combustion aerosol.

What does elevated SP, VIP, and NGF tell us?

 

OSLUND K. ET AL. ACTIVATION OF NEUROKININ-1 RECEPTORS DURING OZONE INHALATION CONTRIBUTES TO EPITHELIAL INJURY AND REPAIR. AM J RESPIR CELL MOL BIOL 39:279-88 2008:

"...C fibers induce central nervous system - mediated reflexes and also release neuropeptides upon activation, including substance P, neurokinin (NK) A, and calcitonin gene-related peptide (Maggi 1995). Substance P has been shown to be increased in human nasal mucosa and airways after exposure to ozone (Schierhorn 2002, Hazbun 1993)...

...airway epithelial cells expressing NK-1 receptors are distributed down the entire length of the airway...

...substance P acting via NK-1 receptors is an important mediator in orchestrating airway epithelial cell death and proliferation after acute ozone exposure...

...substance P primes and activates human neutrophils for superoxide, H2O2, and nitric oxide production (Sterner-Kock 1999, Tanabe 1996)...

...the pivotal role that the activation of c-fibers, with the subsequent release of substance P, plays in the complex cascade of events that are initiated by the acute inhalation of ozone. This role is not limited to reflex responses, such as rapid shallow breathing, but includes modulation of cellular injury and subsequent proliferation of epithelial cells during repair..."

 

COSTA S. ET AL. INVOLVEMENT OF SENSORY NERVES AND TRPV1 RECEPTORS IN THE RAT AIRWAY INFLAMMATORY RESPONSE TO TWO ENVIRONMENTAL POLLUTANTS: DIESEL EXHAUST PARTICLES (DEP) AND 1,2-NAPHTHOQUINONE (1,2-NQ). ARCH TOXICOL 84(2):109-117 2010:

"...The environmental chemical 1,2-naphthoguinone (1,2-NQ) is implicated in the exascerbation of airway diseases induced by exposure to diesel exhaust particles (DEP), which involves a neurogenic-mediated mechanism...

...DEP and 1,2-NQ-induced plasma extravasation...mediated by the endogenous release of the pro-inflammatory neuropeptide substance P. This peptide is most usually found in the peripheral sensory c-fibers and its main receptor (NK1) is widely distributed in the cells body...

...in addition to the NK1 receptor (and its endogenous agonist neurokinin A; NKA) plays a role in the inflammatory response evoked by DEP and 1,2-NQ...(Cho 2004, Xia 2004)..."

 

NILIUS B. ET AL. TRANSIENT RECEPTOR POTENTIAL CATION CHANNELS IN DISEASE. PHYSIOL REV 87:166-217 2007:

"...The major neuropeptides involved in neurogenic inflammation are SP, CGRP, and neuropeptide Y (NPY). Proalgesic, proinflammatory mediators include NGF, protons, histamine, cytokines, chemokines, glutamate, and ATP...

...TRPV1, TRPA1, and TRPM8 are all expressed in sensory neurons in the DRG, TG, and NG. More than 50% of DRG neurons express TRPV1, largely in association with substance P (SP), calcitonin gene-related peptide (CGRP), and the high-affinity nerve growth factor (NGF) receptor TrkA..."

 

DEERING-RICE ET AL. ELECTROPHILIC COMPONENTS OF DIESEL EXHAUST PARTICLES (DEP) ACTIVATE TRANSIENT RECEPTOR POTENTIAL ANKYRIN-1 (TRPA1): A PROBABLE MECHANISM OF ACUTE PULMONARY TOXICITY FOR DEP. CHEM RES TOXICOL 24;6:950-9 2011:

"...A number of studies have correlated responses to urban PM, including DEP with activation of airway sensory neurons, particularly C and A beta fibers that express Transient  Receptor Potential Ankyrin-1 (TRPA1), TRP Vanilloid-1 (TRPV1), and substance P (Hazari 2011, Costa 2010, Anand 2008, Nassenstein 2008, Kobayashi 2005)...

...TRPA1 and V1 are members of the superfamily of ion channels, and numerous TRP receptors including TRPA1, V1-4, and M8 are highly expressed in the respiratory tract where they can function as environmental sensors...

...TRPA1, M8, and V1-4 all respond to specific chemical irritants (Vriens 2009, Venkatachalam 2007, Voets 2005) and activation of either TRPA1 or V1 in pulmonary sensory nerves causes neurogenic inflammation via the release of substance P (SP) and neurokinin A (NKA) (Baraldi 2010)...

...TRPV1, V3, V4, and M8, but seemingly not TRPA1 or V2, are also expressed by airway epithelial cells, and activation of TRPV1 (Teles 2009, Agopyan 2004, 2003, Veronesi 2003, 2001, 2000, Oortgiesen 2000) and TRPM8 (Sabnis 2008) in these cells by prototype agonists and select forms of environmental PM is coupled with proinflammatory cytokine/chemokine production and apoptosis..." 

 

References

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Cho A. et al. Determination of 4 quinones in diesel exhaust particles, SRM1649A and atmospheric 2.5. Aer Sc Tech 38:1-14 2004

Costa S. et al. Involvement of sensory nerves and TRPV1 receptors in the rat airway inflammatory response to two environmental pollutants: diesel exhaust particles (DEP) and 1,2-naphthoquinone (1,2-NQ). Arch Toxicol 84(2):109-117 2010

Deering-Rice et al. Electrophilic components of diesel exhaust particles (DEP) activate transient receptor potential ankyrin-1 (TRPA1): a probable mechanism of acute pulmonary toxicity for DEP. Chem Res Toxicol 24;6:950-9 2011

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