Abstract
Environmental particulate matter (PM) pollutants adversely affect human health, but the molecular basis is poorly understood. The ion channel transient receptor potential vanilloid-1 (TRPV1) has been implicated as a sensor for environmental PM and a mediator of adverse events in the respiratory tract. The objectives of this study were to determine whether TRPV1 can distinguish chemically and physically unique PM that represents important sources of air pollution; to elucidate the molecular basis of TRPV1 activation by PM; and to ascertain the contributions of TRPV1 to human lung cell and mouse lung tissue responses exposed to an insoluble PM agonist, coal fly ash (CFA1). The major findings of this study are that TRPV1 is activated by some, but not all of the prototype PM materials evaluated, with rank-ordered responses of CFA1 > diesel exhaust PM > crystalline silica; TRP melastatin-8 is also robustly activated by CFA1, whereas other TRP channels expressed by airway sensory neurons and lung epithelial cells that may also be activated by CFA1, including TRPs ankyrin 1 (A1), canonical 4α (C4α), M2, V2, V3, and V4, were either slightly (TRPA1) or not activated by CFA1; activation of TRPV1 by CFA1 occurs via cell surface interactions between the solid components of CFA1 and specific amino acid residues of TRPV1 that are localized in the putative pore-loop region; and activation of TRPV1 by CFA1 is not exclusive in mouse lungs but represents a pathway by which CFA1 affects the expression of selected genes in lung epithelial cells and airway tissue.
Footnotes
This work was supported by grants from the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES017431], and the 2011 Colgate-Palmolive Postdoctoral Fellowship (to C.E.D.-R.). Development and synthesis of LJO-328 was supported by the National Research Foundation of Korea [R11-2007-107-02001-0] (to J.L.).
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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ABBREVIATIONS:
- PM
- particulate matter
- TRPA1
- transient receptor potential ankyrin-1
- TRPM8
- transient receptor potential melastatin-8
- TRPC4α
- transient receptor potential canonical-4, α variant
- TRPV1
- transient receptor potential vanilloid-1
- TRPV2
- transient receptor potential vanilloid-2
- TRPV3
- transient receptor potential vanilloid-3
- TRPV4
- transient receptor potential vanilloid-4
- IL
- interleukin
- AITC
- allyl isothiocyanate
- GSK1016790A
- N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide
- LJO-328
- N-(4-tert-butylbenzyl)-N′-(1-[3-fluoro-4-(methylsulfonylamino)phenyl]ethyl)thiourea
- BEAS-2B
- human bronchial epithelial cells
- NHBE
- normal human bronchial epithelial cells
- LHC-9
- Lechner and LaVeck media
- CFA1
- power plant coal fly ash
- CFA2
- laboratory-generated-coal fly ash
- DEP
- diesel exhaust particles
- MUS
- Min-U-Sil 5 μM, crystalline silica
- DD
- desert dust particulate
- HEK
- human embryonic kidney
- TRPV1-OE
- TRPV1-overexpressing BEAS-2B cells
- PBS
- phosphate-buffered saline
- PBS-T
- PBS/Tween 20
- PCR
- polymerase chain reaction
- qPCR
- quantitative real-time PCR
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- GADD153
- growth arrest and DNA damage induced gene-153
- MIP
- macrophage inflammatory protein
- ANOVA
- analysis of variance.
- Received September 23, 2011.
- Accepted December 8, 2011.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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