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 (Isc). However, fluoranthene (1–100 μM) applied in the apical compartment potentiated Isc 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 Isc 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 (IK) 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 IK 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.
Footnotes
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This work was supported by Research Grant Funds from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Hibino Memorial Research Fund, and the Aichi Health Promotion Foundation (to Y.I.).
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DOI: 10.1124/jpet.103.059089.
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ABBREVIATIONS: PAH, polycyclic aromatic hydrocarbon; BMT, bumetanide; 8Br-cAMP, 8-bromo-cAMP; CFTR, cystic fibrosis transmembrane conductance regulator; ChTx, charybdotoxin; DEP, diesel exhaust particle; DNDS, 4,4′-dinitrostilbene-2,2′-disulfonic acid; FLT, fluoranthene; ISO, isoproterenol; NBC1, 4,4′-dinitrostilbene-2,2′-disulfonic acid-sensitive Na+-2HCO3– cotransporter; NKCC1, bumetanide-sensitive Na+-K+-2Cl– cotransporter; PD, potential difference; PKA, protein kinase A; PSS, physiological saline solution; Isc, short-circuit current; DMSO, dimethyl sulfoxide; hIK-1 channel, human intermediate conductance Ca2+-activated K+ channel.
- Received August 24, 2003.
- Accepted November 4, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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