MCS ae Etiology: Airway Reactivity

[michael edward badolato jr]

TRPA1 and TRPV1 may go in hand.

 NASSENSTEIN C. ET AL. EXPRESSION AND FUNCTION OF THE ION CHANNEL TRPA1 IN VAGAL AFFERENT NERVES INNERVATING MOUSE LUNGS J PHYSIOL 586;6:1595-604 2008:

"...Both TRPA1 and TRPV1 may contribute to the development of hypersensitivity to noxious stimulations (i.e. hyperalgesia) (Lamotte 1992, Obata 2005, Bautista 2006, Kwan 2006, Dhaka 2006). In addition TRPA1 is activated by certain environmental irritants such as acrolein (Bautista 2006) that fail to activate TRPV1..."

 

TAYLOR-CLARK T. & UNDEM B. OZONE ACTIVATES AIRWAY NERVES VIA THE SELECTIVE STIMULATION OF TRPA1 CHANNELS. J PHYSIOL 588;3:423-3 2010: 

"...The airways are densely innervated by sensory nerves, the majority of which are afferent C-fibres adapted to detect noxious stimuli (Carr & Undem 2003)...

...transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankryin 1 (TRPA1) are ion channels responsible for the action potential initiation in nociceptive nerves in response to a wide range of inflammatory mediators and noxious irritants (Bessac 2008)...

...ozone evokes high-frequency action potential discharge in broncho-pulmonary C-fibres, and this is a direct effect that occurs via the gating of TRPA1 channels within the C-fibre membranes..."

 

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..."

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 (22):795-810 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...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)..."

 

It appears that TRPA1 may be a most principle receptor - channel activation may closely match chemical reactivity of MCS - they have been shown indispensable for producing head pain. 

 

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)..."

 

KUNKLER P. ET AL. TRPA1 RECEPTORS MEDIATE ENVIRONMENTAL IRRITANT-INDUCED MENINGEAL VASODILITATION. PAIN 152;1:38-44 2011:

"...the site of action of air-borne environmental irritants is TRPA1 receptor on trigeminal nerve terminals in the epithelium of nasal mucosa. The expression of TRPV1 receptors in trigeminal neurons innervating the nasal mucosa has been demonstrated by receptor binding (Rinder 1996) and immunocytochemical studies (Damann 2006, Dinh 2003)...

...Although the initial exposure to air-borne environmental pollutants is the nasal and respiratory epithelium, it is not certain how this leads to meningeal blood vessel dilatation.

As topical (dural) administration of CGRP antagonist blocks the effects of nasally administered TRPA1 agonists on blood flow we presume that the vasodilatation is mediated by CGRP release from perivascular nerve terminals within the meninges.

Activation of trigeminal neurons innervating the nasal mucosa may propagate the signal to the meninges via trigeminal nerve collaterals as trigeminal neurons innervating the nasal cavity have collaterals projecting back into the cranium (Finger 1993).

Intraganglionic transmission (Ulrich-Lai 2001) may transmit the signal from nasal innervating neurons to nearby trigeminal neurons which innervate the meninges...

...In summary, our results demonstrate that TRPA1 receptor activation by environmental irritants stimulates CGRP release from trigeminal neurons and increases cerebral blood flow and may contribute to headache associated with environmental irritants..."

 

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...

...our observations identify umbellone, via its selective TRPA1-agonism, as a trigeminovascular stimulator...for the headache-inducing properties of California bay laurel...a similar pathway may represent the underlying mechanism responsible for headache crises triggered in sensitive people by a series of compounds present in environmental pollutants and botanical perfumes/odours (Blau and Solomon 1985, Kelman 2007, Friedman 2009)..." 

 

IRLBACHER K. & MEYER B. NASALLY TRIGGERED HEADACHE. NEUROLOGY 58:294 2002:  

"...This case suggests that the trigeminal system can play a major role in headache, probably associated with increased trigeminal afferent activity from the nasal mucosa (Ottaviani 1995)..."

 

The experience of sore eyeballs - whether eyes closed or not during exposure - may indicate transmission via nerve pathways - interaction of opthalmic, trigeminal, and olfactory.

 

FINGER T. & BOTTGER B. PERIPHERAL PEPTIDERGIC FIBERS OF THE TRIGEMINAL NERVE IN THE OLFACTORY BULB OF THE RAT. J COMP NEUROL 1;334(1):117-24 1993: 

"...the peripheral branches of the ophtalmic branch of the trigeminal nerve enter the olfactory bulb along with the olfactory nerve and terminate in the glomerular layer along with the olfactory neurons..."

 

TRPA1 may also be major in asthma.

 

CACERES A. ET AL. A SENSORY NEURONAL ION CHANNEL ESSENTIAL FOR AIRWAY INFLAMMATION AND HYPEREACTIVITY IN ASTHMA. PNAS 106;22:9099-9104 2009: 

"...TRPA1-activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma. Endogenous TRPA1 agonists, including reactive oxygen species and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma...

...Our data suggest that TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways, driving asthmatic airway inflammation following inhaled allergen challenge... 

...We show that genetic deletion of TRPA1 or pharmacological channel inhibition diminishes allergen-induced inflammatory leukocyte infiltration, mucus production, cytokine and chemokine levels, and airway hyperreactivity. Trpa1 -/- mice also showed impaired acute and inflammatory neuropeptide release in the airways. In contrast, all aspects of asthmatic airway inflammation were normal in Trpv1 -/- mice..."

References 

Agopyan N et al. Negatively charged 2 and 10 micron particles activate vanilloid receptors, increase cAMP, and induce cytokine release. Tox and Appl Pharm 186(2): 63-76 2003

Andre E. et al. Cigarette smoke-induced neurogenic inflammation is mediated by alpha, beta-unsaturated aldehydes and the TRPA1 receptor in rodents. J Clin Invest 118:2574-82 2008

Baeza-Squiban A. et al. Diesel exhaust particles increase NFkB DNA binding activity and c-fos proto-oncogene expression in human bronchial epithelial cells. Tox In Vitro 13 817-22 1999

Bains J. & Shaw C. Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Brain Res Rev 25:335-58 1997

Bandell M. et al. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41:849-57 2004

Bang S. et al. Transient receptor potential A1 mediates acetaldehyde-evoked pain sensation . Eur J Neurosc 26:2516-23 2007

Baulig A. et al. Role of Paris PM2.5 components in the pro-inflammatory response induced in airway epithelial cells. Tox 261: 126-35 2009.

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 L671-679 2003a

Bautista D. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124: 1269-82 2006

Bayram H. et al. The effect of diesel exhaust particles on cell function and release of inflammatory mediators from human bronchial epithelial cells in vitro. Am J Resp Cell Mol Biol 18:441-48 1998

Bedard A. and Parent A. Evidence of newly generated neurons in the human olfactory bulb. Dev Brain Res 151: 159-68 2004

Berg N.D. et al. Genetic susceptibility factors for multiple chemical sensitivity revisited. Int J Hyg Env H 213: 131-39 2010.

Bessac B. & Jordt S. Breathtaking TRP channels : TRPA1 and TRPV1 in airway chemosensation and reflex control. Phys 23:360-70 2008

Bessac B. et al. TRPA1 is a major oxidant sensor in murine airway sensory neurons. J Clin invest 118:1899-1910 2008a

Bessac B. et al. TRPA1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases. FASEB J 23;4:1102-14 2009

Blau J. & Solomon F. Smell and other sensory disturbances in migraine. J Neurol 232:275-76 1985

Boland S. et al. Mechanisms of GSM-CSF release by diesel exhaust particles in human airway epithelial cells. Am J Phys 278: L25-32 2000

Boland S. et al. Diesel exhaust particles are taken up by human airway epithelial cells in vitro and after cytokine production. Am J Phys 276: L604-13 1999

Bolt H.M. & Their R. Relevance of the deletion polymorphisms of the glutathione-s-transferases GSTT1 and GSTM1 in pharmacology and toxicology. Curr Drug Metab 7:613-28 2006

Bolton J. et al. Role of quinones in toxicology. Chem Res Tox 13:135-60 2000

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 

Bonvallot V. et al. Activation of transcription factors by diesel exhaust particles in human bronchial epithelial cells in vitro. Inhal Tox 12:359-64 2000

Brone B. et al. Tear gases CN, CR, and CS are potent activators of the human TRPA1 receptor. Tox Appl Pharm 231: 150-6 2008

Burtscher H. et al. Characterization of particles in combustion engine exhaust J Aerosol Sci 29:389-96 1998

Burtscher H. and Schmidt-Ott A. In situ measurement of adsorption and condensation of polyaromatic hydrocarbons on ultrafine c particles by means of photoemission. J Aerosol Sci 17:699-703

Cadle S.H et al. Composition of light duty motor vehicle particulat... in the Denver, Colorado area. Env Sc Tech 33;14: 2328-39 1999

Caceres A. et al. A sensory neuronal ion channel essential for airway inflammation and hypereactivity in asthma. PNAS 106;22:9099-9104 2009

Chung H. et al. Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev 8:18-30 2009

Dai Y. et al. Sensitization of TRPA1 by PAR 2 contributes to the sensation of inflammatory pain. J Clin Invest 117:1979-87 2007

Dalle-Donne I. et al. Biomarkers of oxidative damage in human disease. Clin Chem 52:601-23 2006

Damann N. et al. Chemosensory properties of murine nasal and cutaneous trigeminal neurons identified by viral tracing. BMC Neurosc 7:46 2006

Datla K.P. Short term supplementation with plant extracts rich in flavonoids protect nigrostriated dopaminergic neurons in a rat model of Parkinsons disease. Am Coll Nutr 26;4:341-49 2007

Deluca C. et al. Biological definition of multiple chemical sensiti... from redox state and cytokine profiling and not from polymorphisms of xenobiotic metabolizing enzymes. Tox and Appl Pharm 248: 285-92 2010

Deluca C. et al. The search for reliable biomarkers of disease in multiple chemical sensitivity and other environmental intolerances. Int J Env Res Pub H 8: 2770-97 2011.

Dhaka A. et al. TRP ion channels and temperature sensation. Ann Rev Neurosc 29:135-61 2006

Dinh Q. et al. Expression of substance P and vanilloid receptor (VR1) in trigeminal sensory neurons projecting to the mouse nasal mucosa. Neuropeptides 37:245-50 2003

Dinis P. Anandamide-evoked activation of vanilloid reeceptor I contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis. J Neurosc 24:11253-263 2004

Escalera J. et al. TRPA1 mediates the noxious effects of natural sesquiterpene deterrents. J Biol Chem 283:24136-44 2008

Finger T. & Bottger B. Peripheral peptidergic fibers of the trigeminal nerve in the olfactory bulb of  the rat. J Comp Neurol 1;334(1):117-24 1993

Fisher-Wellman K.H. and Bloomer R.J. Exacerbated postprandial oxida...

stress induced by the acute intake of a lipid meal compared to isoenergetically administered carbohydrate, protein, and mixed meals in healthy young men. Am Coll Nutr 29;4:373-81 2010

Friedman D. & De ver Dye T.  Migraine and the environment. Headache 49: 941-52 2009

Fung J. et al. Cytochrome P4501A1 in rat peripheral blood lymphocytes: inducibility in vivo and bioactivation of benzo[a]pyrene in the Salmonella typhimurium mutagenicity assay in vitro. Mutat Res 438:1-12 1999

Gavett S.H. et al. Capsaicin receptor antagonist and c-fiber depletion reduce pulmonary responses to particulate matter in BALB/c mice. The Toxicologists 18:405 1998

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

Gerde P. et al. Benzo{a}pyrene at an environmentally relevant dose is slowly absorbed by, and extensively metabolized in, tracheal epithelium. Carcinogenesis 18:1825-32 1997

Gerde P. et al. Particle-associated polycyclic aromatic hydrocarbons - a reappraisal of their possible role in pulmonary carcinogenesis. Toxical Appl Pharmacol 108:1-13 1991

Goldstone J. et al. The chemical defensome: environmental sensing and response genes in the Strongylocentrotus purpuratus genome. Dev Biol 300:366-84 2006

Halliwell B. & Cross C. Oxygen derived species: their relation to human disease and environmental stress. EHP 102 (Suppl 10):5-12 1994

Harmsen A. et al. The role of macrophages in particle translocation from lungs to lymph nodes. Sci 230:1277-80 1985

Hayes J. et al. Glutathione transferases. Ann Rev Pharm Tox 45:51-88 2005

Hayes A. et al. Effects of neonatal administration of capsaicin on nociceptive thresholds in the mouse and rat. J Pharm Pharmacol 33;3:183-85 1981

Hinman A. et al.TRP channel activation by reversible covalent modification. Proc Nat Acad Sc USA 103:19564-568 2006

Holroyd K. et al. Genetic modeling of susceptibility to nitrogen dioxide-induced lung injury in mice. Am J Physiol 273;1-3:L595-602 1997

Ichinose T. et al. Murine strain differences in allergic airway inflammation and immunoglobulin production by a combination of antigen and diesel exhaust particles. Tox 122;3:183-92 1997

Inoue K-i. et al. Effects of nanoparticles on antigen-related airway inflammation in mice. Resp Res 6:106 2005

Inoue T. & Bryant B. Multiple types of sensory neurons respond to irritating volatile organic compounds (VOCs): calcium fluorimetry of trigeminal ganglion neurons. Pain 117:193-203 2005

Irlbacher K. & Meyer B. Nasally triggered headache. Neurology 58:294 2002

Jordt S. et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260-65 2004

Jung C.G. Psychological Types. Princeton University Press and in the Portable Jung Viking Press 1921

Kelman I. The triggers or precipitants of the acute migraine attack. Cephalagia 27:394-402 2007

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 J Hyg Env H 207:2 159-63 2004.

Kittelson D.B. Engines and nanoparticles: a review. J Aerosol Sci 29: 575-88 1998

Kleeberger S. Genetic susceptibility to ozone exposure. Tox Lett 82-83:295-300 1995

Kleeman M.J. et al. Size and composition distribution of fine particle matter emitted from woodburning, meat charbroiling, and cigarettes. Env Sc Tech 33;20: 3516-23 1999

Kumagai Y. et al. Generation of reactive oxygen species during interaction of diesel exhaust particle components with NADPH-cytochrome reductase and involvement of the bioactivation in the DNA damage. Free Rad Biol Med 222:479-87 1997

Kumagai Y. et al. Apparent inhibition of superoxide dismutase activity in vitro by diesel exhaust particles. Free Rad Biol Med 18:365-71 1995

Kunkler P. et al. TRPA1 receptors mediate environmental irritant-induced meningeal vasodilitation. Pain 152;1:38-44 2011

Kwan K. et al. TRPA1 contributes to cold, mechanical, and chemical nociception but it is not essential for hair-cell transduction. Neuron 50:277-289 2006

LaMotte R. et al. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol 448: 749-764 1992

Lewis J. et al. Trigeminal uptake and clearance of inhaled manganese chloride in rats and mice. Neurotox 26: 113-23 2005

Li N. et al. Induction of heme oxygenase-1 expression in macrophages by diesel exhaust particle chemicals and quinones via the antioxidant-responsive element. J Immunol 165: 3393-3401 2000

Lucchini R.G. et al. Neurological impacts from inhalation of pollutants and the nose-brain connection. Neurotox (2011) doi:10.1016/j.neuro.2011.12.001 in press

Lundborg M. et al. Ability of rabbit alveolar macrphages to dissolve metals. Exp Lung Res 7:11-22 1984

Macpherson L. et al. Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445:541-45 2007

Matsui Y. et al. Tracking the pathway of diesel exhaust particles from the nose to the brain by x-ray florescense analysis. Spectrochimica Acta Part B 64: 796-801 2009

McNamara C. et al. TRPA1 mediates formalin-induced pain. Proc Nat Acad Sc USA 104:31525-30 2007

Meggs W.J. Hypothesis for induction and propagation of chemical sensitivity based on biopsy studies. Env H Perspect 105(2): 473-78 1997

Meggs W.J. et al. Nasal pathology and ultrastructure in patients with chronic airway inflammation (RADS and RUDS) following an irritant exposure. J Tox Clin Tox 34;4: 383 1996

Meggs W.J. and Cleveland Jr. C.H. Rhinolaryngoscopic examination of patients with multiple chemical sensitivity syndrome. Arch Env H 48: 1-14 1993

Merck Manual of Diagnosis and Therapy 17th Ed. Drug Input and Disposition; Metabolism. Chapter 298: pg 2563 Merck Research Laboratories 1999

Miyabara Y. et al. Murine strain differences in airway inflammation caused by diesel exhaust particles. Eur Resp J 11: 291-98 1998

Miyabara Y. et al. Diesel exhaust enhances allergic airway inflamma... and hyperesponsiveness in mice. Am J Resp Crit Care Med 157: 1138-44 1998a

Mohankumar S.M.J. et al. Particulate matter, oxidative stress and neurotoxicity. Neurotox 29: 479-88 2008

Molliere M.et al. Metabolism of benzo[a]pyrene in the combined rat liver-lung perfusion system. Tox 45:143-54 1987

Nassenstein C. et al. Expression and function of the ion channel TRPA1 in vagal afferent nerves innervating mouse lungs. J Physiol 586;6:1595-604 2008

Nassini R. et al. The 'headache tree' via umbellone and TRPA1 activates the trigeminovascular system. Brain doi:10 1093/brain/awr272  2011

Natusch D.F.S. and Tomkins P.A. Theoretical consideration of the adsorption of polynuclear aromatic hydrocarbon vapor onto fly ash in a coal-fired power plant. In Jones P.W. and Freudenthal R.I. (eds) Polynuclear Aromatic Hydrocarbons, Ravan Press, New York, NY 3:145-53 1978
Nielsen G.D. Mechanisms of activation of the sensory irritant receptor by airborne chemicals. Crit Rev Tox 21;3:183-208 1991

Nel A.E. et al. The role of particulate pollutants in pulmonary inflammation and asthma:evidence for the involvement of organic chemicals and oxidative stress. Curr Opin Pulm Med 7: 20-26 2001.

Nielsen G.D. Mechanisms of activation of the sensory irritant receptor by airborne chemicals. Crit Rev Tox 21:3:183-208 1991

Nyberg K. et al. Estimation of PH in individual alveolar macrophage phagolysosomes. Exp Lung Res 15:499-510 1989

Obata K. et al. TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J Clin Invest 115:2393-2401 2005

Oortgiesen et al. Residual oil fly ash and charged polymers activate epithelial cells and nociceptive sensory neurons. Am J Physiol Lung Cell Mol Physiol 278: L683-95 2000

Ottaviani F. Centro-peripheral etiopathogenesis of primary headache triggered nasally. Ital J Neurol Sci 16:35-9 1995

Pakkanen T.A. et al. Size distributions of mass and chemical compon... in street-level and rooftop PM1 particles in Helsinki. Atmosph Env 37: 1673-90 2003

Pereira W. Chlorination studies AM. II. The reaction of aqueous hypochlorous acid with alpha-amino acids and dipeptides. Biochem Biophys Acta 313:170-80 1973

Prior M. et al. Capsaicin pretreatment modifies hydrogen sulphide-induced pulmonary injury in rats. Tox Pathol 18;2:279-88 1990

Rinder J. et al. Capsaicin-, resiniferatoxin-, and lactic acid-evoked vascular effects in the pig nasal mucosa in vivo with reference to characterization of the vanilloid receptor. Pharm Tox 78:327-35 1996

Roy et al. Susceptibility to pollutant-induced airway inflammation is neurogenically mediated. EPA EIMS Metadata report 59754 2000

Satoh H. et al. Inhibitory effects of capsazepine and SR 48968 on citric acid-induced bronchoconstriction in guinea-pigs. Eur J Pharm 236;3:367-72 1993

Scheerens H. et al. The involvement of sensory neuropeptides in toluene diisocyanate-induced tracheal hyperreactivity in the mouse airways. Br J Pharm 119;8:1665-71 1996

Shafer F. & Buettner G. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free rad Biol Med 30:1191-1212 2001

Society of Automotive Engineers. Schematic of diesel particles and vapor phase compounds. SAE Paper no. 940233 1994

Steerenberg P.A. et al. Diesel exhaust particles induced release of interleukin 6 and 8 by (primed) human bronchial epithelial cells (BEAS 2B) in vitro. Exp Lung Res 24: 85-100 1998

Stone V. et al. The role of oxidative stressin the prolonged inhibitory effect of ultrafine carbon black on epithelial cell function. Tox in vitro 12:649-59 1998

Symanowicz P. et al. Lack of role for the vanilloid receptor in response to several inspired irritant air pollutants in the C57B1/6J mouse. Neurosc Lett 362:150-3 2004

Taylor-Clark T. & Undem B. Ozone activates airway nerves via the selective stimulation of TRPA1 ion channels. J Physiol 588;3:423-33 2010

Thomas R. et al. ETS1, NFkB and AP-1 synergistically transactivate the human GM-CSF promoter. Oncogene 14:Z845-55 1997 

Thompson C.L et al. Relationships among benzo[a]pyrene metabolism benzo[a]pyrene-dial-epoxide DNA adduct formation and sister chromatid exchanges in human lymphocytes from smokers and nonsmokers. Cancer Res 49:6501-11 1989
Ulrich-Lai Y. Capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from rat trigeminal ganglion: evidence for intraganglionic neurotransmission. Pain 91:219-26 2001

Veronesi B. & Oortgiesen M. The TRPV1 receptor: target of toxicants and therapeutics. Tox Sc 89(1):1-3 2006

Veronesi B. et al. Effects of subchronic exposure to concentrated ambient particles VII Degeneration of dopaminergic neurons in APO E-1 mice. Inhal Tox 17; 4-5: 235-41 2005

Veronesi B. et al. Electrostatic charge activates inflammatory vanilloid (VR1) receptors. Neurotox 24: 463-73 2003

Veronesi B. et al. The surface charge of visible particulate matter predicts biological activation in human bronchial epithelial cells. Tox and Appl Pharm 178: 144-54 2002a

Veronesi B. et al. Particulate matter inflammation and receptor sensitivity are target cell specific. Inhal Tox 14(2): 159-83 2002b

Veronesi B. and Oortgiesen M. Neurogenic inflammation and particulate matter (PM) air pollutants. Neurotox 22: 795-810 2001

Veronesi B. et al. Vanilloid capsaicin receptors influence inflammatory sensitivity in response to particulate matter. Tox Appl Pharm 15;169(1): 66-76 2000

Veronesi B. et al. Particulate matter initiates inflammatory cytoki... by activation of capsaicin and acid receptors in a human bronchial epithelial cell line. Tox and Appl Pharm 154: 106-15 1999a

Veronesi B.et al. Neuropeptides and capsaicin stimulate the release of inflammatory cytokines in a human bronchial epithelial cell line. Neuropep 33;6: 447-56 1999b

Yang Y. et al. Endothelial glutathione-s-transferase A4-4 protects against oxidative stress and modulates iNOS expression through NF-kappa B translocation. Tox Appl Pharm 230:187-96 2008

Yeadon M. et al. Mechanisms contributing to ozone-induced bronchial hyperreactivity in guinea-pigs. Pulm Pharm 5;1:39-50 1992

Yeh H.C. et al. Comparisons of calculated respiratory tract deposition of particles based on the proposed NCRP model and the new ICRP66 MODEL. Aer Sci Tech 25:134-40 1996

Zhang L. Differential susceptibility to ozone-induced airways hyperreactivity in inbred strains of mice. Exp Lung Res 21;4:503-18 1995

Ziedinski H. et al. Modeling the interactions of particulates with epithelial lining fluid antioxidants. Am J Phys 277:L719-26 1999