Multiple Chemical Sensitivity Etiology
Airway Genetics and Ambient Combustion Aerosol
MCS 4 Top Studies in a Nutshell
MCS is usually very high levels of neurogenic inflammation - including release of inflammatory cytokines, chemokines, and growth factors
Mohankumar 2008 - "...release of inflammatory cytokines and mediators from respiratory epithelia into the systemic circulation..."
Veronesi 2001 - "...a more protracted release of of inflammatory cytokines from sensory neurons - the pro-inflammatory cytokines IL-6, IL-8, and TNF alpha...enhanced and prolonged inflammatory events...increased inflammatory response..."
Calderon-Garciduenas 2000 - "...their phenotype is altered to one that secretes cytokines, mediators, chemokines, and growth factors..."
Bascom 1992 (MCS 6) "...the observation that the airway can release cytokines...flu-like symptoms, low grade fever, and fatigue that...usually begin several hours after the exposure and last up to 48 hours...a type of acute phase response...cytokines are now recognized as responsible..."
elevated plasma markers of inflammation
Deluca 2010 - "...The activities of erythrocyte catalase and GST were lower, whereas GPX was higher than normal. Both reduced and oxidized glutathione were decreased, whereas nitrites/nitrates were increased in the MCS groups. The MCS fatty acid profile was shifted to saturated compartment and IFNgamma, IL-8, IL-10, MCP-1, PDGFbb, and VEGF were increased..."
"...Notwithstanding the absence of genetic defects in CYPs, recent studies have increasingly implicated various inflammatory stimuli, first of all, pro-inflammatory cytokines (Chun 2002, Nadin 1995, Tapner 1996, Tinel 1999) to cause changes in the activities and expression levels of CYPs through nitric oxide signalling (Chun 2002, Stadler 1994). For example, drug metabolizing CYPs such as CYP3A4 and CYP2B6, which are constitutively expressed in human mono nuclear cells, have been significantly repressed by IFN Gamma or IL-2 (Liptrott 2009)...
...Our results suggest that serious and multiple dysfunctions of chemical defense systems found in MCS patients may mainly not depend on genetic defects, but instead may rely on non-genetic modifications of metabolizing/antioxidant enzyme expression and/or activity, mediated by redox active agents such as NO and inflammatory cytokines...
...Dysfunction of two major antioxidant enzymes and depletion of glutathione inevitably leads to severe oxidative stress and impaired elimination of phase 1 oxidation metabolites. Excessive amounts of hydrogen peroxide due to catalase deficiency will initiate a non enzymatic free radical driven chain reaction of lipid peroxidation implicated in a number of human pathologies..."Found elevated in MCS patients (Dantoft 2014)
Kimata 2004 - MCS people had 2 1/2 - 4X plasma substance P, 4- 6X vasoactive intestinal peptide, 7-11X nerve growth factor, and twice histamine compared to normals.
arising from airway epithelial damage and exposed c-fiber sensory nerves
Bessac 2008 - "...Chemical exposure studies in animals showed that reactive irritants can cross-desensitize each other’s ability to initiate respiratory defensive responses...C fibers lack myelination, allowing rapid access for chemical stimuli along the fiber path through the tissue... persistent inflammatory neuronal sensitization... production of a wide range of proinflammatory mediators known to sensitize airway sensory fibers...
"...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)..."
Mohankumar 2008 - "... inflammatory cytokines/chemokines being released from the chronically inflamed airways..."
Castranova 2002 - guinea pigs reached a peak in nerve fiber density 24 to 48 hours after the exposure returning to near baseline at 96 hours.
Lee and Pisarri 2001 - especially potent stimulators of C-fiber nerves include nicotine and other components of tobacco smoke and residue; and the hydroxyl radical in the gas phase of woodsmoke.
Bonham 2001 - "...sensory nonmyelinated C-fibers innervating the lung...the responses evoked through the local axon reflex include bronchoconstriction, mucous secretion, and microvascular leak..."
Veronesi 2001 "...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..."
"...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...".
Meggs 1997, 1996 - "...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..."
Meggs1993 - "...Neurogenic inflammation is now a well defined physiological mechanism by which mediators are directly released from sensory neurons to produce vasodilitation, edema, and other manifestations of inflammation. The nerve fibers have been identified as slow velocity C-fibers and the regulation of neurogenic inflammation has been studied...important regulators of inflammation, interleukin 1 and interleukin 2, suppress central nervous system activity..."
reactive and measurable
Millquist 2005 - "...after capsaicin provocation the patients showed a significant increase in NGF which was related to capsaicin cough sensitivity...SHR (sensory hypereactivity) is real and measurable, demonstrating a pathophysiology in the airways of these patients compared to healthy subjects...
Nogami 2004 - When MCS people were exposed to capsaicin - cough occurred 5 times (5 coughs) at a concentration .150 far less than both the control group 1.120 and the chronic cough group .630.
In a continuous environment of combustion byproduct aerosol including particle agglomerates with adsorbed hydrocarbons and singlet nonagglomerated nanoparticles
Mgt 104 Respirators and Adsorbed Hydrocarbons
MCS 13 Deluca 2010 Overlooks Airway Genetics
MCS 9 Airway Origin: PM and a Defective Scrubber
MCS 10 Credible Proof: the Study of all Studies
Gerde 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)..."
Baulig A. 2009 - "...In vitro, epithelial cells and macrophages (particles target cells) exposed to PM, developed a pro-inflammatory response characterized by the release of inflammatory cytokines (Baulig 2003a, Hetland 2004, Jalava 2008)..."
Baulig 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)..."
BONVALLOT 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)..."
Block 2009 - ".. .air pollution may rank as the most prevalent source of environmentally induced inflammation and oxidative stress.. Air pollution effects cross from the periphery to the brain through systemic inflammation, and translocation of nanoparticles to the brain, where both the physical characteristics of the particle itself and the toxic compounds adsorbed on the particle may cause damage..."
Agopyan 2003 - Negatively charged 2- and 10-μm particles activate vanilloid receptors, increase cAMP, and induce cytokine release.
Veronesi 2003 - electrostatic charge activates inflammatory vanilloid (VR1) receptors.
"...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..."
2000 - "...particle laden AMs (alveolar macrophages) produce reactive oxygen species and inflammatory mediators...PM10 (particulate matter less than 10 microns) has free radical activity and causes lung inflammation and epithelial injury (Li 1996)...
"...The results obtained support that nano-sized DEPs do in fact translocate to the central nervous system through the olfactory nerve..."
Lewis 2005 - "...These data support the conclusion that a similar pattern of uptake may occur within the trigeminal system as has been observed in the olfactory system..."
"...into the CNS in concentrations greater than those found with systemic distribution and without penetrating the blood-brain barrier..."
"...These data underscore the importance of considering routes of toxicant entry that allow for bypassing of the protection afforded by the blood brain barrier, and the importance of understanding the conditions under which these pathways are operative..."
with genetic vulnerability in the airway epithelial cell population and its sensory innervation usually a co-factor
Eberling 2009 - "...In conclusion, we found an increased familial occurrence of perfume-related respiratory symptoms where 35% of phenotypic variation was due to additive genetic effects and 65% was due to individual specific environmental effects...".
Veronesi 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)..."
2000 - "...DRG neurons, cultured from BALB/c and B6 neonates, were loaded with Fluo-3 AM and exposed to the prototype irritants, acid pH (5.0, 6.5), or capsaicin (3, 10 μM). Analysis of their increases in intracellular calcium showed that significantly higher numbers of BALB/c neurons responded to these prototype irritants, relative to B6 neurons.
Morphometric analysis of BALB/c neurons, histochemically stained with cobalt to label neurons bearing capsaicin-sensitive receptors, showed a significantly higher level of stained neurons relative to B6 neurons.
Finally, semiquantitative RT-PCR showed a higher expression of VR1 receptor mRNA in DRG and spinal cord taken from neonatal BALB/c mice relative to B6 mice.
Taken together, these data suggest that capsaicin and acid-sensitive irritant receptors, located on somatosensory cell bodies and their nerve fiber terminals, subserve PM-induced airway inflammation and are quantitatively different in responsive and nonresponsive mouse strains..."
Roy 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..."
Miyabara 1998 - "...In conclusion, murine strain differences in response to air pollutants and allergens seem to be related to antigen-specific immunoglobulin GI production and cytokine production in the lungs..."
Jung 1921 - C.G Jung reported that the introverted intuitive had an extraordinary dependence on sense impressions as a counterweight to the rarified air of the intuitive cast of mind - with hypersensitivity of the sense organs and hypochondriacal symptoms. Jung didn't know this was actually a physical disease - MCS.
neuropeptides, VRI receptors, and acid sensitive pathways on c-fiber sensory neurons lining the nasal and upper pulmonary airways critical to the homeostatic regulation of inflammatory response and activity of immune system cells
resulting in disabling near immediate and secondary complications including increased nitric oxide and peroxynitrite (Deluca 2010, Pall 2002),
lipid peroxidation (Badolato 2011c, Deluca 2010),
dysfunction of chemical defense systems - metabolizing and antioxidant enzymes including decreased erythrocyte catalase and glutathione-s-transferase activity, severe glutathione depletion, and cytokine mediated suppression of cytochrome P450 and aryl hydrocarbon receptor activity (Deluca 2010),
central nervous system effects
Nassini 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..."
Orriols 2009 - "...Chemical exposure caused neurocognitive impairment, and SPECT brain dysfunction particularly in odor-processing areas, thereby suggesting a neurogenic origin of MCS..."
Calderon-Garciduenas 2008 - "...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)..."
and porphryrin abnormalities
Hahn 1997 - "...Although patients with MCSS may, at times, have modest increases in urinary coproporphyrin excretion, this is a common finding found in many asymptomatic subjects or patients with diverse other conditions (eg, diabetes mellitus, heavy alcohol use, liver disease, and many kinds of anemia). Such secondary coproporphyrinuria does not indicate the existence of coproporphyria..."
Daniell 1997 - "...It has been hypothesized that several otherwise unexplained chemical-associated illnesses, such as multiple chemical sensitivity syndrome, may represent mild chronic cases of porphyria or other acquired abnormalities in heme synthesis... individual cases or case series characterized by relatively mild increases in porphyrin excretion and/or decreases in activity of various heme-synthesis enzymes...there is currently no convincing evidence that these illnesses are mediated by a disturbance of heme synthesis; it is premature or unfounded to base clinical management on such explanations unless laboratory data are diagnostic for porphyria..."
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