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Am J Physiol Cell Physiol 279: C461-C479, 2000;
0363-6143/00 $5.00
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Vol. 279, Issue 2, C461-C479, August 2000

Pharmacological modulation of ion transport across wild-type and Delta F508 CFTR-expressing human bronchial epithelia

Daniel C. Devor1, Robert J. Bridges1, and Joseph M. Pilewski1,2

Departments of 1 Cell Biology and Physiology and 2 Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Forskolin, UTP, 1-ethyl-2-benzimidazolinone (1-EBIO), NS004, 8-methoxypsoralen (Methoxsalen; 8-MOP), and genistein were evaluated for their effects on ion transport across primary cultures of human bronchial epithelium (HBE) expressing wild-type (wt HBE) and Delta F508 (Delta F-HBE) cystic fibrosis transmembrane conductance regulator. In wt HBE, the baseline short-circuit current (Isc) averaged 27.0 ± 0.6 µA/cm2 (n = 350). Amiloride reduced this Isc by 13.5 ± 0.5 µA/cm2 (n = 317). In Delta F-HBE, baseline Isc was 33.8 ± 1.2 µA/cm2 (n = 200), and amiloride reduced this by 29.6 ± 1.5 µA/cm2 (n = 116), demonstrating the characteristic hyperabsorption of Na+ associated with cystic fibrosis (CF). In wt HBE, subsequent to amiloride, forskolin induced a sustained, bumetanide-sensitive Isc (Delta Isc = 8.4 ± 0.8 µA/cm2; n = 119). Addition of acetazolamide, 5-(N-ethyl-N-isopropyl)-amiloride, and serosal 4,4'-dinitrostilben-2,2'-disulfonic acid further reduced Isc, suggesting forskolin also stimulates HCO3- secretion. This was confirmed by ion substitution studies. The forskolin-induced Isc was inhibited by 293B, Ba2+, clofilium, and quinine, whereas charybdotoxin was without effect. In Delta F-HBE the forskolin Isc response was reduced to 1.2 ± 0.3 µA/cm2 (n = 30). In wt HBE, mucosal UTP induced a transient increase in Isc (Delta  Isc = 15.5 ± 1.1 µA/cm2; n = 44) followed by a sustained plateau, whereas in Delta F-HBE the increase in Isc was reduced to 5.8 ± 0.7 µA/cm2 (n = 13). In wt HBE, 1-EBIO, NS004, 8-MOP, and genistein increased Isc by 11.6 ± 0.9 (n = 20), 10.8 ± 1.7 (n = 18), 10.0 ± 1.6 (n = 5), and 7.9 ± 0.8 µA/cm2 (n = 17), respectively. In Delta F-HBE, 1-EBIO, NS004, and 8-MOP failed to stimulate Cl- secretion. However, addition of NS004 subsequent to forskolin induced a sustained Cl- secretory response (2.1 ± 0.3 µA/cm2, n = 21). In Delta F-HBE, genistein alone stimulated Cl- secretion (2.5 ± 0.5 µA/cm2, n = 11). After incubation of Delta F-HBE at 26°C for 24 h, the responses to 1-EBIO, NS004, and genistein were all potentiated. 1-EBIO and genistein increased Na+ absorption across Delta F-HBE, whereas NS004 and 8-MOP had no effect. Finally, Ca2+-, but not cAMP-mediated agonists, stimulated K+ secretion across both wt HBE and Delta F-HBE in a glibenclamide-dependent fashion. Our results demonstrate that pharmacological agents directed at both basolateral K+ and apical Cl- conductances directly modulate Cl- secretion across HBE, indicating they may be useful in ameliorating the ion transport defect associated with CF.

cystic fibrosis; 5-trifluoromethyl-1-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benzimidazole-2-one; genistein; 1-ethyl-2-benzimidazolinone; 8-methoxypsoralen; cystic fibrosis transmembrane conductance regulator


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