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TOXICOLOGY

Effects of Fluoranthene, a Polycyclic Aromatic Hydrocarbon, on cAMP-Dependent Anion Secretion in Human Airway Epithelia

Division of Respiratory Diseases, Department of Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

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 µM) 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 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 Ca²⁺ concentration ([Ca²⁺]_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 [Ca²⁺]_i. These results suggest that fluoranthene switches from cAMP-dependent secretion to Cl^– secretion through the hIK-1 channel, whose sensitivity to protein kinase A may be up-regulated by the sustained [Ca²⁺]_i elevation produced by this chemical.

Address correspondence to: Dr. Yasushi Ito, Division of Respiratory Diseases, Department of Medicine, Nagoya Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: itoyasu{at}med.nagoyau.ac.jp

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