Abstract
Environmental particulate pollutants (PM) adversely affect human health, but the molecular basis is poorly understood. The ion channel 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 if TRPV1 can distinguish chemically and physically unique PM that represent 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: TRPV1 is activated by some, but not all of the prototype PM materials evaluated, with responses to CFA1>diesel exhaust PM>crystalline silica; TRPM8 is also robustly activated by CFA1, while other TRP channels expressed by airway sensory neurons and lung epithelial cells that may also be activated by CFA1, including TRPA1, C4α, M2, V2, V3, or 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 impacts the expression of selected genes in lung epithelial cells and airway tissue.
- Received September 23, 2011.
- Revision received December 8, 2011.
- Accepted December 8, 2011.
- The American Society for Pharmacology and Experimental Therapeutics