title: Effects of fluoranthene, a polycyclic aromatic hydrocarbon, on cAMP-dependent anion secretion in human airway epithelia.
abstract: The human respiratory tract is constantly exposed to polycyclic aromatic hydrocarbons (PAHs) through inhalation of atmospheric pollutants. We examined the effects of three PAHs (benzo[a]pyrene, anthracene, and fluoranthene) on the airway ion transport, which is essential for lung defense and normal airway function, using human airway epithelia (Calu-3). These three PAHs had no significant effect on the basal short-circuit current (I(sc)). However, fluoranthene (1-100 microM) applied in the apical compartment potentiated I(sc) in response to cAMP-related agents (isoproterenol, forskolin, and 8-bromo-cAMP). The effects of fluoranthene were unaffected by ellipticine, a PAH receptor antagonist. Estimation of the anionic composition of I(sc) revealed that isoproterenol increased both HCO(3)(-) and Cl(-) transport in the control, whereas it potentiated only Cl(-) transport in the presence of fluoranthene. The fluoranthene-induced modulations of these anion transporters were counteracted by charybdotoxin (ChTx, a hIK-1 channel blocker). Fluoranthene gradually augmented the ChTx-sensitive K(+) current (I(K)) across the basolateral membrane, accompanied by a sustained increase in the cytosolic Ca(2+) concentration ([Ca(2+)](i)). In the presence of fluoranthene, however, a much larger hIK-1-dependent I(K) was identified by the application of 8-bromo-cAMP without concomitant elevation of [Ca(2+)](i). These results suggest that fluoranthene switches from cAMP-dependent HCO(3)(-) secretion to Cl(-) secretion through the hIK-1 channel, whose sensitivity to protein kinase A may be up-regulated by the sustained [Ca(2+)](i) elevation produced by this chemical.
authors: Division of Respiratory Diseases, Department of Medicine, Nagoya Graduate School of Medicine, Japan. itoyasu@med.nagoya-u.ac.jp
authors: Yasushi
authors: Y
authors: Ito
authors: Masami
authors: M
authors: Son
authors: Shinji
authors: S
authors: Sato
authors: Takamasa
authors: T
authors: Ohashi
authors: Masashi
authors: M
authors: Kondo
authors: Kaoru
authors: K
authors: Shimokata
authors: Hiroaki
authors: H
authors: Kume
mesh_terms: D000838:Anions / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018118:Chloride Channels / Q000378:metabolism; D000242:Cyclic AMP / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects* / Q000378:metabolism; D005449:Fluorenes / Q000494:pharmacology*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D027361:Organic Anion Transporters / Q000187:drug effects / Q000378:metabolism; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated; D012137:Respiratory System / Q000166:cytology
chemical_list: D000838:Anions; D018118:Chloride Channels; D004791:Enzyme Inhibitors; D005449:Fluorenes; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D027361:Organic Anion Transporters; D011084:Polycyclic Aromatic Hydrocarbons; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; C007738:fluoranthene; D000242:Cyclic AMP; D002118:Calcium