Negatively charged 2- and 10-μm particles activate vanilloid receptors, increase cAMP, and induce cytokine release

Exposure to airbome pollutants, such as particulate matter (PM), is associated with increased mortality and morbidity. Indirect evidence suggested that PM-induced responses could be initiated by the activation of proton-gated receptors, including vanilloid receptors (VRs) and acid-sensitive ion channels (e.g. ASICS), We tested this hypothesis by characterizing the effects of 10- and 2-mum polystyrene carboxylate-modified particles (PC10 and PC2) on HEK 293 cells expressing VR1 receptors, rat trigeminal ganglion (TG) neurons, and BEAS-2B airway epithelial cells. Zeta potential measurements revealed that these particles are negatively charged, meaning that when they adhere to a membrane they can lower the surface pH and activate proton-gated receptors, Both types of PCs induced currents and/or elevated intracellular Ca2+ in cells that were capsaicin sensitive (CS). In about 70% of CS neurons, 10 muM capsazepine (CPZ), a VR antagonist, blocked PC-induced responses. In TG neurons in which VRs were blocked or desensitized, PCs induced an amiloride-inhibitable inward cur-rent having the characteristics of ASIC-mediated currents. Incubation of TG neurons with either capsaicin or PCs produced a CPZ-sensitive increase in cyclic AMP and cytokine (IL-6) release. In summary, we provide unequivocal evidence demonstrating that negatively charged PCs could activate VR1 and other proton-gated receptors. These data suggest that pharmacological manipulation of such receptors could prevent the physiological actions of PMs. (C) 2003 Elsevier Science (USA). All rights reserved.