MCS ab Etiology: Particulate Vector

[michael edward badolato jr]

Clean Diesel: Public Health Nightmare

 

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 PROINFLAMMATORY 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)..."

 

Cause and Exascerbation of Cardio-pulmonary Disease

 

LI J. ET AL. TRPV4-MEDIATED CALCIUM INFLUX INTO HUMAN BRONCHIAL EPITHELIA UPON EXPOSURE TO DIESEL EXHAUST PARTICLES. EHP 119: 784-93 2011:

"...DEP injures respiratory epithelia via a luminal -apical unloading mechanism of DEP organics delivered by carbonaceous nanoparticles...
...the particles' carbonaceous cores are coated with thousands of organics and heavy metals. Because large numbers of hazardous chemicals are present on DEP, its pathological effects on human airways are pleiotropic. We and others have found that DEP evokes the secretion of matrix metallo-proteinase-1 (MMP-1) from human bronchial epithelia (Li 2009, Amara 2007). Matrix metalloproteinase-1 (MMP-1) plays a role in tissue remodeling during development, inflammation, migration of inflammatory and malignant cells, and COPD and emphysemia pathogenesis (Segura-Valdez 2000). It also has neurotropic effects, possibly enhancing sensitization of airway-innervating sensory neurons, contributing to airway hypersensitization and chronic cough (Conant 2004)...

...TRPV4-p19s, a human genetic polymorphism previously identified as a COPD susceptibility locus (Zhu 2009), increases MMP-1 activation via increased Ca-2+ influx, providing a mechanistic link between human airway epithelia signaling, airway disease and air pollution...

...TRPV4-p19s as a gain-of-function Ca-2+ permeable channel in a human respiratory epithelia cell line, in response to DEP, links COPD pathogenesis to pathologically increased Ca2+ influx into human respiratory epithelia elicited by a globally relevant air pollutant (DEP)...

...our results imply that two human genetic polymorphisms are linked to respiratory health, TRPV4-p19s and MMP-1(-1607G/GG), thus highlighting the concept of disease susceptibility as a function of genetic "makeup" combined with environmental insults..."

 

HAZARI M. ET AL. TRPA1 AND SYMPATHETIC ACTIVATION CONTRIBUTE TO INCREASED RISK OF TRIGGERED CARDIAC ARRHYTHMIAS IN HYPERTENSIVE RATS EXPOSED TO DIESEL EXHAUST. EHP 119:951-57 2011:

"...a single exposure to particulate matter (PM) or gaseous air pollutants has the potential to "sensitize" the heart to subsequent arrhythmogenic stimuli, which is further worsened by the presence of underlying cardiovascular disease (Hazari 2009)...

...the airways are innervated by sensory nerves bearing transient receptor potential (TRP) channels; namely, member A1 (TRPA1), and member V1 (TRPV1), which detect different types of noxious chemicals, including many of those found in the complex mixtures of common air pollutants such as DE. Activation of these nerves by airborne irritants such as ozone or acrolein causes centrally mediated autonomic "imbalance", which produces ventilatory, pulmonary, and cardiovascular function changes (Bessac 2008, Ghelfi 2008, Bautista 2006)..."

 

Causitive Role in Alzheimer's and Parkinson's

 

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:

... exposure to significant amounts of air pollutants including UFPM and PM2.5 produces neuroinflammation and altered innate immune responses in crucial brain target anatomical areas...ultrafine PM could play a role in the enhancement rate of protein fibrillation affecting Abeta42 and alpha-synuclein (Linse 2007)...

...Long-term exposure to air pollution should be considered a risk factor for both Alzheimer's and Parkinson's diseases, and APOE beta 4 allele carriers could have a higher risk of developing AD if they reside in a polluted environment..."

References 

Adamson A.W. Physical Chemistry of Surfaces. John Wiley, New York, NY 1982

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

Amara N. et al. Diesel exhaust particles induce matrix-metalloprotease-1 in human lung epithelial cells via a NADP(H) oxidase/NOX4 redox-dependent mechanism. Am J Physiol Lung Cell Mol Physiol 293;1:L170-81 20077

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

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 1986

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

Calderon-Garciduenas L. et al. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulationof amyloid beta-42 and alpha-synuclein in children and young adults. Tox Pathol 36: 289-310 2008

Calderon-Garciduenas L. et al. Brain inflammation and Alzheimer's-like pathology in individuals exposed to severe air pollution. Tox Pathol 32: 650-58 2004

Calderon-Garciduenas L. et al. Air pollution and brain damage. Tox Pathol 30: 373-89 2002

Calderon-Garciduenas L. et al. Respiratory tract pathology and cytokine imbalance in clinically healthy children chronically and sequentially exposed to air pollutants. Med hyp 55(5): 373-78 2000

Calderon-Garciduenas L., Maronpot R.R. et al. DNA damage in nasal and brain tissues of canines exposed to air pollutants is associated with evidence of chronic brain inflammation and neurodegeneration. Tox Pathol 31: 524-38 2003

Calderon-Garciduenas L., Mora-Tiscareno A. et al. Respiratory damage in children exposed to urban pollution. Pediatr Pulmonal 36: 148-61 2003

Calderon-Garciduenas L. et al. Respiratory tract pathology and cytokine imbalance in clinically healthy children chronically and sequentially exposed to air pollutants. Med Hyp 55(5): 373-378 2000

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

Conant K. et al. Matrix-metalloproteinase-1 interacts with neuronal integrins and stimulates dephosphorylation of Akt. J Biol Chem 279(9):8056-62 2004

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

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.

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

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

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

Ghelfi E. et al. Cardiac oxidative stress and electro-physiological changes in rats exposed to concentrated ambient particles are mediated by TRP-dependent pulmonary reflexes. Tox Sc 102;2:328-36 2008

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

Hazari M. et al. A single exposure to particulate or gaseous air pollution increases the risk of aconitine-induced cardiac arrhymthias in hypertensive rats. Tox Sc 112(2):532-42 2009

Hazari M. et al. TRPA1 and sympathetic activation contribute to increased risk of triggered cardiac arrhythmia in hypertensive rats exposed to diesel exhaust. EHP 119:951-57 2011

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

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

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

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

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

Li J. et al. Diesel exhaust particles activate the matrix-metalloproteinase-1 gene in human bronchial epithelia in a beta-arrestin-dependent manner via activation of RAS. EHP 117:400-09 2009

Li J. et al. TRPV4-mediated calcium influx into human bronchial epithelia upon exposure to diesel exhaust particles. EHO 119: 784-93 2011

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

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

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

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

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

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

Segura-Valdez L. et al. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 117(3):684-94 2000

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

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

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

Zhu G. et al. Association of TRPV4 gene polymorphisms with chronic obstructive pulmonary disease. Hum Mol Gen 18(11):2053-62 2009

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