Pharmacological treatment of the ion transport defect in cystic fibrosis

被引:31
作者
Roomans, GM [1 ]
机构
[1] Uppsala Univ, Dept Med Cell Biol, S-75123 Uppsala, Sweden
关键词
4-phenylbutyrate; airway epithelium; amiloride; bicarbonate; chaperones; chloride transport; cystic fibrosis; cystic fibrosis transmembrane conductance regulator; genistein; purinergic agonists; sodium transport; xanthines;
D O I
10.1517/13543784.10.1.1
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Cystic fibrosis (CF) is a lethal monogenetic disease characterised by impaired water and ion transport over epithelia. The lung pathology is fatal and causes death in 95% of CF patients. The genetic basis of the disease is a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel. The most common mutation, Delta F508, results in a protein that cannot properly be folded in the endoplasmic reticulum, is destroyed and hence does not reach the apical cell membrane. This paper will discuss those pharmacological approaches that are directed at correcting the defect in ion transport. At present, no clinically effective drug is available, although research has defined areas in which progress might be made. These are the following: (1) the drug 4-phenylbutyrate (4PBA) increases the expression of Delta F508-CFTR in the cell membrane, probably by breaking the association between Delta F508-CFTR and a chaperone; (2) a number of xanthines, in particular 8-cyclopentyl-1, 3-dipropylxanthine (CPX), are effective in activating CFTR, presumably by direct binding and also possibly by correcting the trafficking defect; (3) the isoflavone genistein can activate both wild-type and mutant CFTR, probably through direct binding to the channel; (4) purinergic agonists (ATP and UTP) can stimulate chloride secretion via a Ca2+-dependent chloride channel and in this way compensate for the defect in CFTR, but stable analogues will be required before this type of treatment has clinical significance; (5) treatment with inhaled amiloride may correct the excessive absorption of Na+ ions and water by airway epithelial cells that appears connected to the defect in CFTR; although clinical tests have not been very successful so far, amiloride analogues with a longer half-life may give better results. The role of CFTR in bicarbonate secretion has not yet been established with certainty, but correction of the defect in bicarbonate secretion may be important in clinical treatment of the disease. Currently, major efforts are directed at de developing a pharmacological treatment of the ion transport defect in CF, but much basic research remains to be done, in particular, with regard to the mechanism by which defective CFTR is removed in the endoplasmic reticulum by the ubiquitin-proteasome pathway, which is a central pathway in protein production and of significance for several other diseases apart from CF.
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页码:1 / 19
页数:19
相关论文
共 161 条
[1]   Adenosine triphosphate - Established and potential clinical applications [J].
Agteresch, HJ ;
Dagnelie, PC ;
van den Berg, JWO ;
Wilson, JHP .
DRUGS, 1999, 58 (02) :211-232
[2]  
AKIYAMA T, 1987, J BIOL CHEM, V262, P5592
[3]  
Akiyama T., 1991, METHOD ENZYMOL, V201, P362
[4]   Activation of ΔF508 CFTR in a cystic fibrosis respiratory epithelial cell line by 4-phenylbutyrate, genistein and CPX [J].
Andersson, C ;
Roomans, GM .
EUROPEAN RESPIRATORY JOURNAL, 2000, 15 (05) :937-941
[5]  
ANDERSSON C, 2000, P 13 INT CYST FIBR C, P93
[6]   ACUTE AND LONG-TERM AMILORIDE INHALATION IN CYSTIC-FIBROSIS LUNG-DISEASE - A RATIONAL APPROACH TO CYSTIC-FIBROSIS THERAPY [J].
APP, EM ;
KING, M ;
HELFESRIEDER, R ;
KOHLER, D ;
MATTHYS, H .
AMERICAN REVIEW OF RESPIRATORY DISEASE, 1990, 141 (03) :605-612
[7]   Direct activation of cystic fibrosis transmembrane conductance regulator channels by 8-cyclopentyl-1,3-dipropylxanthine (CPX) and 1,3-diallyl-8-cyclohexylxanthine (DAX) [J].
Arispe, N ;
Ma, JJ ;
Jacobson, KA ;
Pollard, HB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (10) :5727-5734
[8]   CFTR involvement in chloride, bicarbonate, and liquid secretion by airway submucosal glands [J].
Ballard, ST ;
Trout, L ;
Bebök, Z ;
Sorscher, EJ ;
Crews, A .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 1999, 277 (04) :L694-L699
[9]   POSSIBLE REGULATION OF CFTR-CHLORIDE CHANNELS BY MEMBRANE-BOUND PHOSPHATASES IN PANCREATIC DUCT CELLS [J].
BECQ, F ;
FANJUL, M ;
MERTEN, M ;
FIGARELLA, C ;
HOLLANDE, E ;
GOLA, M .
FEBS LETTERS, 1993, 327 (03) :337-342
[10]   cAMP- and Ca2+-independent activation of cystic fibrosis transmembrane conductance regulator channels by phenylimidazothiazole drugs [J].
Becq, F ;
Verrier, B ;
Chang, XB ;
Riordan, JR ;
Hanrahan, JW .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (27) :16171-16179