MCS 2a Etiology Detailed

[michael edward badolato jr]

CONTENT OF THIS FORUM HAS BEEN ENTIRELY DISTRIBUTED AMONG FORUMS MCS ab,ac,ad,ae & af

MCS usually originates from the airway epithelium and its sensory innervation - which has defects due to genetic disposition and environmental exposure.

 

Consumption of oxygen during normal cellular metabolism produces reactive oxygen and nitrogen species (RONS) most inactivated by antioxidant defenses including reduced glutathione, ascorbic acid, alpha tocopheral and enzymes superoxide dismutase, catalase, and glutathione peroxidase (Fisher-Wellman 2010, Datla 2007, Bains 1997, Halliwell 1994).

 

Balanced formation and inactivation of pro-oxidant species determine intracellular redox environment - represented by the ratios of interconvertable reduced (GSH) to oxidized (GSSG) form of glutathione - responsible for the initiation and regulation of many physiological processes within living systems.

 

Cellular functions that respond to shift in redox - favoring oxidizing or reducing conditions - include signal transduction, DNA and RNA synthesis, protein synthesis, enzyme activation, and regulation of the cell cycle (Shafer 2001).

 

A chronic oxidizing shift in redox - involving increased RONS production and decreased antioxidant defense - oxidative stress - has a role in many and varied disease conditions (Chung 2009, Dalle Donne 2006, Halliwell 1994).

 

A defective airway releases excessive inflammation subject to the detox enzyme chemical defense systems concerned with both xenobiotics and endogenous products such as aldehydes resulting from lipid peroxidation and the deactivation of reactive oxygen species (Yang 2008, Bolt 2006, Hayes 2005). It can be imagined they would be suppressed, inhibited, or overwhelmed in an extended chain reaction of oxidative stress (Deluca 2010).

 

DELUCA C. ET AL BIOLOGICAL DEFINITION OF MULTIPLE CHEMICAL SENSITIVITY FROM REDOX STATE AND CYTOKINE PROFILING AND NOT FROM POLYMORPHISMS OF XENOBIOTIC-METABOLIZING ENZYMES. TOX AND APPLIED PHARM 248;285-92 2010 :

 

"...the ubiquitous chemical defense network (phase I-II xenobiotic metabolizing and antioxidant enzymes) appears very early in the evolution and handles low molecular weight inorganic and organic xenobiotics, as well as endogenous non-protein signaling molecules, mediators of inflammation, degradation products, and toxic products of cellular metabolism (Goldstone 2006)..."

 

Phase I reactions form a new or modified functional group or a cleavage (oxidation, reduction, hydrolysis). These are non synthetic - the most important are cytochrome P450 isoenzymes (CYPs) that transfer electrons and catalyze oxidation.

Phase II reactions are synthetic - involving conjugation with an endogenous compound forming metabolites more polar and readily excreted by the kidneys and liver in urine and bile (Merck 1999).

 

Phase I and II enzymes apply to organic compounds including hydrocarbons of the ambient combustion aerosol.

 

GERDE P. ET AL. THE RAPID ALVEOLAR ABSORPTION OF DIESEL SOOT-ADSORBED BENZO[a]PYRENE: BIOAVAILABILITY, METABOLISM, AND DOSIMETRY OF AN INHALED PARTICLE-BORNE CARCINOGEN. CARCINOGENESIS 22;5: 741-49 2001:

 

During combustion particles are generated and PAHs (polycyclic aromatic hydrocarbons) form in the gas phase. When the exhaust cools - PAHs adsorb or condense on the particles (Burtscher 1998).

There are two principal fractions of adsorbed PAHs: one is quickly desorbed - and the other retained on particles for a long time (Gerde 1991, Burtscher 1986, Adamson 1982, Natusch 1978).

 

Approx 80% of rapidly desorbed PAHS are deposited on the thin alveolar type 1 epithelium deep in the lung (Yeh 1996) and become systemic quickly with blood concentration peaking in several minutes.

 

3/4 of blood activity from the rapidly absorbed B[a]P (benzo[a]pyrene) used in Gerde 2001 ceased in 10 minutes - nearly all within 30 - and by one hour completely leveled - mostly into conjugated phase ll metabolites (Fung 1999, Thompson 1989, Molliere 1987).

 

In contrast, the remaining 20%of rapidly desorbed PAHs "...are deposited, slowly absorbed, and extensively metabolized in airway epithelium at prolonged elevation of the local tissue concentration (Gerde 1997)..."

 

Over 5 months later particles in the lung and lymph nodes had only 37 and 59% of B[a]P desorbed - mostly during the initial rapid release - with the exception of more desorption from particles translocated to the lymph nodes - possibly due to environment within macrophages (Nyberg 1989, Harmsen 1985, Lundborg 1984).

 

In airway epithelial cells a complexity of transduction and transcription factors (NFkB, MAPK, XRE, ARE, NrF2) and modification of cellular redox - are involved with the secretion of inflammatory cytokines and induction of Phase I and II gene expression including CYP1A1 and NQO-1 (Baulig 2003a) - from a point of view excluding the sensory innervation.

 

BAULIG A. ET AL. INVOLVEMENT OF REACTIVE OXYGEN SPECIES IN THE METABOLIC PATHWAYS TRIGGERED BY DIESEL EXHAUST PARTICLES IN HUMAN AIRWAY EPITHELIAL CELLS. AM J PHYSIOL LUNG CELL MOL PHYSIOL 285:L671-79 2003a

 

"...In airway epithelial cells, DEP (diesel exhaust particles) via their organic components (polycyclic aromatic hydrocarbons PAHS including benzo[a]pyrene desorbed from the carbonaceous core), modify the cellular redox state...induce phase I  (CYP1A1) and phase II (NQO-1) gene expression and can be metabolized,,,numerous genes implicated in detoxification...activated via xenobiotic responsive element) and ARE (antioxidant responsive element) as well as in the secretion of proinflammatory cytokines via NFkB responsive element (Bonvallot 2001)..."  

 

The expression of metabolizing enzymes in airway epithelial cells is not unique to MCS - since the search for a genetic explanation concerning phase I and II enzymes found no association that could be applied to the majority of MCS cases (MCS 14, Deluca 2011, 2010, Berg 2010).

 

However, activity of these enzymes is with cost - their induction a struggle to survive - inhalation of combustion byproducts living on the edge - as in the following of Bonvallot 2001 concerning ROS generation and CYPs.

 

BONVALLOT V. ET AL. ORGANIC COMPOUNDS FROM DIESEL EXHAUST PARTICLES ELICIT A PRO-INFLAMMATORY RESPONSE IN HUMAN AIRWAY EPITHELIAL CELLS AND INDUCE CYTOCHROME P450 1A1 EXPRESSION. AM J RESP CELL MOL BIOL 25:515-21 2001:

 

"...DEP (diesel exhaust particles have been shown to generate ROS (reactive oxygen species) leading to the transcription of antioxidant genes such as heme oxygenase-1(HO-1), which are regulated by the antioxidant responsive element (Li 2000, Kumagai 1995)...

...catalytic activities of cytochrome P450 are known to produce ROS directly and also generate biologic reactive intermediates, including quinones, which produce ROS by redox cycling (Bolton 2000)...

...CB (carbonaceous core) exhibit oxidative properties as they deplete the antioxidant defenses in the epithelial lining fluid (Ziedinski 1999) and induce DNA strand scission in plasmidic DNA (Stone 1998)...

...the carbonaceous core could be considered mostly as a vector allowing the entry of organic compounds into the cells and their slow diffusion leading to sustained stimulation of the cells as native diesel exhaust particles-induced NFkB DNA binding started later but was more persistent than that induced by organic extracts of diesel exhaust particles...(Boland 2000, 1999, Bonvallot 2000, Baeza-Squiban 1999, Bayram 1998, Kumagai 1997, Thomas 1997)..."

 

A genetic finding among metabolizing enzymes is not necessary since the factor specific to MCS is the genetic propensity of sensory irritant receptors - their peptidenergic transmission - greater inflammatory release - furthering local tissue damage and setting forth the systemic reaction of oxidative stress.

 

The observation (Jung 1921) that hypersensitivity of the sense organs and hypochondriacal symptoms occurred among genetically determined introverted intuitives may be a strong clue of the genetic basis. Jung referred to an extraordinary dependence on sense impressions as a counterweight to rarified air of the intuitive cast of mind.

 

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 et al 1995), nitrogen dioxide (Holroyd et al 1997), and diesel exhaust (Ichinose et al 1997, Miyabara et al 1998)..."

 

ROY ET AL. SUSCEPTIBILITY TO POLLUTANT-INDUCED AIRWAY INFLAMMATION IS NEUROGENICALLY MEDIATED EPA EIMS METADATA REPORT 59754 2000:

 

"...We have previously shown that the BALB/c mouse strain is responsive to PM-inflammation in contrast to the non-responsive C57/blk (B6) mouse strain.

This differential sensitivity is retained in PM exposed cultures of somatosensory neurons from the dorsal root and trigeminal ganglia that innervate the airways in terms of inflammatory cytokine release.

In the present study, we use RT-PCR, cobalt histochemistry and immunocytochemical techniques to show that the  expression of capsaicin (VR1) and Substance P (NK-1) receptors and the release of inflammatory cytokines and neuropeptides are higher in sensory neurons from BALB/c mice relative to the  B6 strain. 

These data suggest that the strain-specific inflammatory response to PM and other irritants (i.e. capsaicin, acid sensitive) seen in vivo and in vitro models of PM inflammation is subserved by sensory  and neuropeptide receptors..."

 

Recent studies may be closer to a precise explanation of the reactivity.

 

VERONESI B. & OORTGIESEN M. THE TRPV1 RECEPTOR: TARGET OF TOXICANTS AND THERAPEUTICS. TOX SC 89(1): 1-3 2006:

 

"...the transient receptor potential vanilloid receptor (TRPV1) formerly known as vanilloid receptor VR1 was thought to be confined to sensory C nerve cell bodies and fiber terminals...TRPV1 is now known to be broadly expressed in all "port of entry" tissues (e.g., skin, gut, airways, conjunctiva) and the various cell types lining such tissues (i.e., keratinocytes, epithelia, endothelia, etc.)...

...The TRPV1 is activated by various ligand-like agents and a plethora of seemingly unrelated stimuli such as chemical irritants, inflammatory mediators, and tissue damaging stimuli. These include capsaicinoids such as capsaicin, RTX, and olvanil; endogenous ligands such as anandamide (which also activates the cannabinoid 1 receptor); and inflammatory mediators (e.g., phorbol-12-myristate 13-acetate, lipoxygenase products, leukotriene B4, phorbol-12-phenylacetate 13 acetate 20-homovanillate). TRPV1 is also activated by nonselective stimuli: such as high temperature (>43 degrees C), acidic pH (<5.3), intracellular redox states, and electric charge. The precise mechanisms of receptor activation by such agents have not been fully established although such stimuli appear to alter protein conformation and stability through specific amino acid residues on the receptor, which results in ion influx and disruptions of structural gating..."

 

 

BESSAC B. & JORDT S. BREATHTAKING TRP CHANNELS: TRPA1 AND TRPV1 IN AIRWAY CHEMOSENSATION AND REFLEX CONTROL. PHYS 23:360-70 2008:

 

"...TRPV1 is unlikely to represent the major reactive irritant receptor. TRPV1-deficient mice showed normal respiratory sensitivity to electrophilic agents (acrolein) and solvents (styrene)...(Symanowicz 2004)...TRPV1  lacked responsiveness to acrolein (Dinis 2004)...electrophilic irritants activated only a subset of capsaicin-sensitive neurons (Inoue 2005)...

...TRPA1 (transient receptor potential ankyrin 1) is expressed in a subpopulation of TRPV1-expressing c-fiber neurons...

...acrolein (aldehyde in smog and smoke)...is a potent agonist of...TRPA1 channels (Bautista 2006)...cultured sensory neurons from TRPA1-deficient mice lacked any responsiveness to this irritant suggesting that TRPA1 is the sole chemosensory receptor for acrolein (Bautista 2006)...

...TRPA1 is activated by (smoke constituents) methacrolein, methyl vinyl ketone, and croton aldehyde (Andre 2008, Escalera 2008)...oxidizing agents...hypochlorite (chlorine gas)...(Bessac 2008a)...formaldehyde, acetaldehyde, tear gas agents, and industrial isocyanates (Bang 2007, Bessac 2009, Brone 2008, McNamara 2007)...almost all oxidizing and electrophilic chemicals will affect TRPA1 function...endogenous agonists include reactive oxygen species (ROS), hypochlorite, lipid peroxidation products, cyclopentenone prostaglandins, and isoprostanes...

...a potential explanation for the diversity of TRPA1 agonists (Hinman 2006, Macpherson 2007)...TRPA1 is activated through covalent modification of the channel protein (agreement with Veronesi 2006)...

...aldehydes such as acrolein are strong electropliles and react with cysteine residues (amino acid component of protein)...Hypochlorite, hydrogen peroxide, and other reactive oxygen species directly oxidize cysteine thiols to sulfinic and sulfonic groups (Pereire 1973)...

...TRPA1 can be locked into a constitutively active state, indicating saturation of a reactive site (Hinman 2006)...

...three cysteine residues were crucial for channel activation (Macpherson 2007)...activation of TRPA1 by covalent modification through reactive irritants...dose response relationships and activation kinetics of TRPA1 do not conform to standard pharmacological paradigms and are highly dependent on the chemical status of the cellular and tissue environment...

...TRPA1 agonists show wide divergence, sometimes one or two orders of magnitude...TRPA1 agonist activity will depend on the reversible or irreversible nature of the chemical bonds formed and on agonist membrane permeability...

...since most TRPA1 agonist can react with thiols, cellular and extracellular reduced glutathione levels will affect the reach and potency of inhaled airway irritants. Once glutathione is depleted, either as a consequence of disease or during extended exposures, TRPA1 may respond more strongly (Deluca 2010 found MCS people have severe glutathione depletion). With each breath more reactive agonist is delivered, leading to an increase in covalent modifications and heightened TRPA1 activity...robust TRPA1 induced irritation even at low subacute exposure levels...once irreversibly modified channels may remain active for extended periods of time even when the irritant stimulus is removed...(Bessac 2008a)...

...The multiple chemical sensitivity of TRPA1...tissue injury may sensitize TRPA1 channels through inflammatory signaling pathways, thereby establishing prolonged hypersensitivity to multiple reactive chemicals (Bandell 2004, Bautista 2006, Dai 2007, Jordt 2004)..."

 

Returning to Veronesi 2001 reminds - that although TRP channels have been found to express more widely than on sensory c fiber nerves only - there is much higher inflammatory release from receptors on the nerves than of the epithelial cell population - and deenervation hugely reduces inflammatory response.

 

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 [Kimata 2004: SP MCS 105 before 153 after exposure to paint, controls 38 and 39]) 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...

...BALB/c mice were deenervated of polymodal sensory c fibers by neonatal capsaicin treatment. Sensory neurons , dissected from the DGR (dorsal root ganglia of these deenervated animals and exposed to various PM (50mg/ml) or prototype irritants failed to release IL-6 in response - implicating the sensory c fibers as critical to cytokine release in response to PM...(Gavett 1998, Scheerens 1996, Satoh 1993, Yeadon 1992, Nielsen 1991, Prior 1990, Hayes 1981)..."

 

Meggs 1997, 1996,1993,  found MCS patients had airway epithelial damage and multiplied 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....

 

A damaged airway results in CNS effects.

 

NASSINI R. ET AL. THE 'HEADACHE TREE' VIA UMBELLONE AND TRPA1 ACTIVATES THE TRIGEMINOVASCULAR SYSTEM. BRAIN DOI:10 1093/BRAIN/AWR272 2011:

 

"...The California bay laurel...the 'headache tree'...inhalation...can cause severe headache crises...

...monoterpene ketone umbellone, the major volatile constituent...

...umbellone stimulates the transient receptor potential ankryin 1 (TRPA1) channel in a subset of peptidergic nocioceptive neurons (recall Bessac 2008 above), activating the trigeminovascular system...

...in wild-type mice, umbellone elicited excitation of trigeminal neurons and released calcitonin gene-related peptide from sensory nerve terminals. These two responses were absent in TRPA1 deficient mice. Umbellone caused nocioceptive behaviour after stimulation of trigeminal nerve terminals in wild-type, but not TRPA1 deficient mice...

...TRPA1 activation may either be caused directly by umbellone, which diffuses from the nasal mucosa to perivascular nerve terminals in meningeal vessels, or by stimulation of trigeminal endings within the nasal mucosa and activation of reflex pathways...

...present data also strengthen the hypothesis  that a series of agents, including chlorine, cigarette smoke, formaldehyde, and others that are known to be headache triggers and recently identified as TRPA1 agonists, utilize the activation of this channel on trigeminal nerves to produce head pain..." 

 

CALDERON-GARCIDUENAS ET AL. LONG TERM AIR POLLUTION IS ASSOCIATED WITH NEUROINFLAMMATION,  AN ALTERED INNATE IMMUNE RESPONSE, DISRUPTION OF THE BLOOD BRAIN BARRIER, ULTRAFINE PARTICULATE DEPOSITION, AND ACCUMULATION OF AMYLOID BETA-42 AND ALPHA-SYNUCLEIN IN CHILDREN AND YOUNG ADULTS. TOX PATHOL 36: 289-310 2008:

 

"...Breakdown of the nasal respiratory and olfactory epithelium and the BBB (Blood Brain Barrier) facilitates the access of systemic inflammatory mediators and components of air pollution to the central nervous system (CNS) (Calderon-Garciduenas 2004)..."

 

"...A coherent pathway linking exposure to air pollution and brain damage includes a chronic inflammatory process involving the respiratory tract, which results in a systemic inflammatory response with the production of inflammatory mediators capable of reaching the brain; continuous expression of crucial inflammatory mediators in the CNS at low levels; and the formation of reactive oxygen species (ROS) (Calderon-Garciduenas et al 2002, 2004; Calderon-Garciduenas, Maronpot et al 2003; Calderon-Garciduenas, Mora-Tiscareno et al 2003)..."

 

"...sustained exposures to significant levels of air pollutants including UFPM (ultrafine particulate matter) , PM2.5 (less than 2.5 microns), and PM-LPS  produce brain neuroinflammation and neurodegeneration through at least four pathways..."

 

"...1  Induction of upper respiratory, lung epithelial, and endothelial injury leading to persistent chronic inflammation in the respiratory tract and systemic inflammation. The systemic inflammation is accompanied by the production of pro-inflammatory cytokines such as TNF alpha, IL 6 and IL-1beta...these cytokines can activate endothelial cells in the BBB, disrupt the BBB...and trigger cascades...results in increased expression of nitric oxide synthase...and nitric oxide production that opens the BBB..."

 

"...2  We strongly support the importance of the olfactory pathway...since olfactory neurons are loaded with PM...will potentially translate into an abnormality in the limbic system...(Bedard et al 2004)..."

 

"...3  The vagus/trigeminal (Lewis et al 2005) pathways are also crucial, given that PM enters the respiratory and digestive systems..."

 

"...4  Direct access of UFPM to the brain, further accentuating an inflammatory response in the brain parenchyma..."

 

In combination with a genetic predisposition of the airway epithelium and its sensory innervation (Eberling 2009, Veronesi 2001, 2000, Roy 2000, Miyabara 1998, Jung 1921) - MCS is usually caused by exposure to a continuous combustion byproduct aerosol - diesel and other exhaust, woodsmoke, and tobacco smoke - including particle agglomerates with adsorbed hydrocarbons and singlet nonagglomerated nanoparticles Lucchini 2011,  Baulig 2009, Mohankumar 2008, Calderon-Garciduenas 2008, 2000, Inoue 2005, Agopyan 2003, Veronesi 2003, 2002a, 2002b, 2001, 2000, 1999a, 1999b, Oortgiesen 2000, Roy 2000, Pakkanen 2003, Kittelson 1998, Cadle 1999, Kleeman 1999 ,Gerde 2001, 1997, Miyabara 1998a, Steerenberg 1998, Society of Automotive Engineers SAE 940233 1994).

 

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