Effects of fluoranthene, a polycyclic aromatic hydrocarbon, on cAMP-dependent anion secretion in human airway epithelia.
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.
Ito
Yasushi
Y
Division of Respiratory Diseases, Department of Medicine, Nagoya Graduate School of Medicine, Japan. itoyasu@med.nagoya-u.ac.jp
Son
Masami
M
Sato
Shinji
S
Ohashi
Takamasa
T
Kondo
Masashi
M
Shimokata
Kaoru
K
Kume
Hiroaki
H
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
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