Pharmacological Approaches to Correcting the Ion Transport Defect in Cystic Fibrosis

2003 ◽  
Vol 2 (5) ◽  
pp. 413-431 ◽  
Author(s):  
Godfried M. Roomans
Keyword(s):  
Cystic Fibrosis ◽  
Ion Transport ◽  
Transport Defect

Pharmacological modulation of ion transport across wild-type and ΔF508 CFTR-expressing human bronchial epithelia

2000 ◽  
Vol 279 (2) ◽  
pp. C461-C479 ◽  
Author(s):  
Daniel C. Devor ◽  
Robert J. Bridges ◽  
Joseph M. Pilewski
Keyword(s):  
Cystic Fibrosis ◽  
Ion Transport ◽  
Short Circuit ◽  
Primary Cultures ◽  
Short Circuit Current ◽  
Bronchial Epithelium ◽  
Disulfonic Acid ◽  
Wild Type ◽  
Pharmacological Agents ◽  
Transport Defect

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 ΔF508 (ΔF-HBE) cystic fibrosis transmembrane conductance regulator. In wt HBE, the baseline short-circuit current ( I sc) averaged 27.0 ± 0.6 μA/cm2 ( n = 350). Amiloride reduced this I sc by 13.5 ± 0.5 μA/cm2 ( n = 317). In ΔF-HBE, baseline I sc 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 I sc(Δ I sc = 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 I sc, suggesting forskolin also stimulates HCO3 − secretion. This was confirmed by ion substitution studies. The forskolin-induced I scwas inhibited by 293B, Ba2+, clofilium, and quinine, whereas charybdotoxin was without effect. In ΔF-HBE the forskolin I sc response was reduced to 1.2 ± 0.3 μA/cm2 ( n = 30). In wt HBE, mucosal UTP induced a transient increase in I sc (Δ I sc = 15.5 ± 1.1 μA/cm2; n = 44) followed by a sustained plateau, whereas in ΔF-HBE the increase in I sc was reduced to 5.8 ± 0.7 μA/cm2 ( n = 13). In wt HBE, 1-EBIO, NS004, 8-MOP, and genistein increased I sc 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 ΔF-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 ΔF-HBE, genistein alone stimulated Cl− secretion (2.5 ± 0.5 μA/cm2, n = 11). After incubation of ΔF-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 ΔF-HBE, whereas NS004 and 8-MOP had no effect. Finally, Ca2+-, but not cAMP-mediated agonists, stimulated K+ secretion across both wt HBE and ΔF-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.

Pharmacotherapy of the Ion Transport Defect in Cystic Fibrosis

2003 ◽  
Vol 2 (4) ◽  
pp. 299-309 ◽  
Author(s):  
Karl Kunzelmann ◽  
Marcus Mall
Keyword(s):  
Cystic Fibrosis ◽  
Ion Transport ◽  
Transport Defect

Non–invasive liposome–mediated gene delivery can correct the ion transport defect in cystic fibrosis mutant mice

1993 ◽  
Vol 5 (2) ◽  
pp. 135-142 ◽  
Author(s):  
E. W. F. W. Alton ◽  
P. G. Middleton ◽  
N. J. Caplen ◽  
S. N. Smith ◽  
D. M. Steel ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gene Delivery ◽  
Ion Transport ◽  
Mutant Mice ◽  
Non Invasive ◽  
Transport Defect

Cryopreservation of cystic fibrosis nasal epithelium

1988 ◽  
Vol 46 ◽  
pp. 88-89
Author(s):  
J. R. Herlong
Keyword(s):  
Cystic Fibrosis ◽  
Ion Transport ◽  
Nasal Mucosa ◽  
Chloride Ion ◽  
Infectious Complications ◽  
Organ System ◽  
Human Nasal Mucosa ◽  
X Ray ◽  
Chloride Ion Transport ◽  
Transport Defect

Cystic fibrosis (CF) is the most common lethal genetic disease which affects Caucasians. The respiratory system is almost universally affected in CF patients, and the basic defect in this organ system as well as in others appears to be an abnormality of the regulation of chloride ion transport; the transport of other ions may also be either primarily or secondarily affected. Both the nasal mucosa and the lower respiratory tracts of CF patients exhibit this defect, but the nasal mucosa is free of the infectious complications common in the lower tract regions. Electron probe x ray microanalysis (EPXMA) promises to be a useful tool in the investigation, at the cellular and subcellular levels, of this ion transport defect as well as possible defects in the transport of other ions. This report documents the development of techniques for obtaining well-preserved cryosections of human nasal mucosa which are suitable for subsequent EPXMA.

Correction of the ion transport defect in cystic fibrosis transgenic mice by gene therapy

Nature ◽  
1993 ◽  
Vol 362 (6417) ◽  
pp. 250-255 ◽  
Author(s):  
Stephen C. Hyde ◽  
Deborah R. Gill ◽  
Christopher F. Higgins ◽  
Ann E. O. Trezise ◽  
Lesley J. MacVinish ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Transgenic Mice ◽  
Ion Transport ◽  
Transport Defect
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