title: Arsenic alters ATP-dependent Ca²+ signaling in human airway epithelial cell wound response.
abstract: Arsenic is a natural metalloid toxicant that is associated with occupational inhalation injury and contaminates drinking water worldwide. Both inhalation of arsenic and consumption of arsenic-tainted water are correlated with malignant and nonmalignant lung diseases. Despite strong links between arsenic and respiratory illness, underlying cell responses to arsenic remain unclear. We hypothesized that arsenic may elicit some of its detrimental effects on the airway through limitation of innate immune function and, specifically, through alteration of paracrine ATP (purinergic) Ca²+ signaling in the airway epithelium. We examined the effects of acute (24 h) exposure with environmentally relevant levels of arsenic (i.e., < 4 μM as Na-arsenite) on wound-induced Ca²+ signaling pathways in human bronchial epithelial cell line (16HBE14o-). We found that arsenic reduces purinergic Ca²+ signaling in a dose-dependent manner and results in a reshaping of the Ca²+ signaling response to localized wounds. We next examined arsenic effects on two purinergic receptor types: the metabotropic P2Y and ionotropic P2X receptors. Arsenic inhibited both P2Y- and P2X-mediated Ca²+ signaling responses to ATP. Both inhaled and ingested arsenic can rapidly reach the airway epithelium where purinergic signaling is essential in innate immune functions (e.g., ciliary beat, salt and water transport, bactericide production, and wound repair). Arsenic-induced compromise of such airway defense mechanisms may be an underlying contributor to chronic lung disease.
authors.affiliation: Arizona Respiratory Center, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 85724-5030, USA.
authors.forename: Cara L
authors.initials: CL
authors.lastname: Sherwood
authors.forename: R Clark
authors.initials: RC
authors.lastname: Lantz
authors.forename: Jefferey L
authors.initials: JL
authors.lastname: Burgess
authors.forename: Scott
authors.initials: S
authors.lastname: Boitano
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D001151:Arsenic / Q000633:toxicity*; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020013:Calcium Signaling; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000255:Adenosine Triphosphate; D001151:Arsenic