Novel, mechanism-based therapies for cystic fibrosis

Current Opinion in Pediatrics

Volumn 17, Issue 3, 2005, Pages 385-392

  Rubenstein, Ronald C ^a,b  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

Author keywords

Chloride channels; CIC 2; CICA; Cystic fibrosis; Cystic fibrosis transmembrane conductance regulator; Epithelial ion transport; Epithelial sodium channel

Indexed keywords

4 PHENYLBUTYRIC ACID; AMILORIDE; ANTIBIOTIC G 418; APROTININ; BAY 399437; BUTYRIC ACID; CURCUMIN; DENUFOSOL; DURAMYCIN; GENISTEIN; GENTAMICIN; INS 316; LUBIPROSTONE; MUTANT PROTEIN; THAPSIGARGIN; TOBRAMYCIN; TRANSMEMBRANE CONDUCTANCE REGULATOR; ULINASTATIN; UNCLASSIFIED DRUG; URIDINE TRIPHOSPHATE;

CLINICAL TRIAL; COUGHING; CYSTIC FIBROSIS; DOSE RESPONSE; HUMAN; ION TRANSPORT; LUNG ALVEOLUS EPITHELIUM; MOUSE; NONHUMAN; PATHOPHYSIOLOGY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN SYNTHESIS INHIBITION; REGULATORY MECHANISM; REVIEW; SIDE EFFECT; THORAX PAIN; WHEEZING;

ANIMALS; CHILD; CYSTIC FIBROSIS; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; EPITHELIAL CELLS; EPITHELIAL SODIUM CHANNEL; HUMANS; ION TRANSPORT; MUTATION; SODIUM CHANNELS;

EID: 20344363920     PISSN: 10408703     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.mop.0000158846.95469.6f     Document Type: Review

References (126)

1. Rubenstein RC, Zeitlin PL. Use of protein repair therapy in the treatment of cystic fibrosis. Curr Opin Pediatr 1998; 10:250-255.
2. Zeitlin PL. Novel pharmacologic therapies for cystic fibrosis. J Clin Invest 1999; 103:447-452.
3. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 1993; 73:1251-1254.
4. Hamosh A, Rosenstein BJ, Cutting GR. CFTR nonsense mutations G542X and W1282X associated with severe reduction of CFTR mRNA in nasal epithelial cells. Hum Mol Genet 1992; 1:542-544.
5. Hamosh A, Trapnell BC, Zeitlin PL, et al. Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis. J Clin Invest 1991; 88:1880-1885.
6. Shoshani T, Augarten A, Gazit E, et al. Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. Am J Hum Genet 1992; 50:222-228.
7. Kalman YM, Kerem E, Darvasi A, et al. Difference in frequencies of the cystic fibrosis alleles, delta F508 and W1282X, between carriers and patients. Eur J Hum Genet 1994; 2:77-82.
8. Howard M, Frizzell RA, Bedwell DM. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med 1996; 2:467-469.
9. Bedwell DM, Kaenjak A, Benos DJ, et al. Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line. Nat Med 1997; 3:1280-1284.
10. Du M, Jones JR, Lanier J, et al. Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. J Mol Med 2002; 80:595-604.
11. Clancy JP, Bebok Z, Ruiz F, et al. Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. Am J Respir Crit Care Med 2001; 163:1683-1692.
12. Wilschanski M, Famini C, Blau H, et al. A pilot study of the effect of gentamicin on nasal potential difference measurements in cystic fibrosis patients carrying stop mutations. Am J Respir Crit Care Med 2000; 161:860-865.
13. Wilschanski M, Yahav Y, Yaacov Y, et al. Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N Engl J Med 2003; 349:1433-1441.
14. Denning GM, Anderson MA, Amara JF, et al. Processing of mutant cystic fibrosis transmembrane regulator is temperature-sensitive. Nature 1992; 358:761-764.
15. Cheng SH, Gregory RJ, Marshall J, et al. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 1990; 63:827-834.
16. Pasyk EA, Foskett JK. Mutant (delta F508) cystic fibrosis transmembrane conductance regulator Cl- channel is functional when retained in endoplasmic reticulum of mammalian cells. J Biol Chem 1995; 270:12347-12350.
17. Egan ME, Schwiebert EM, Guggino WB. Differential expression of ORCC and CFTR induced by low temperature in CF airway epithelial cells. Am J Physiol 1995; 268:C243-C251.
18. Denning GM, Anderson MP, Amara JF, et al. Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature 1992; 358:761-764.
19. Brown CR, Hong-Brown LQ, Biwersi J, et al. Chemical chaperones correct the mutant phenotype of the delta F508 cystic fibrosis transmembrane conductance regulator protein. Cell Stress Chaperones 1996; 1:117-125.
20. Sato S, Ward CL, Krouse ME, et al. Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. J Biol Chem 1996; 271:635-638.
21. Bebok Z, Venglarik CJ, Panczel Z, et al. Activation of DeltaF508 CFTR in an epithelial monolayer. Am J Physiol 1998; 275:C599-C607.
22. Zhang XM, Wang XT, Yue H, et al. Organic solutes rescue the functional defect in delta F508 cystic fibrosis transmembrane conductance regulator. J Biol Chem 2003; 278:51232-51242.
23. Cheng SH, Fang SL, Zabner J, et al. Functional activation of the cystic fibrosis trafficking mutant delta F508-CFTR by overexpression. Am J Physiol 1995; 268:L615-L624.
24. Moyer BD, Loffing-Cueni D, Loffing J, et al. Butyrate increases apical membrane CFTR but reduces chloride secretion in MDCK cells. Am J Physiol 1999; 277:F271-F276.
25. Rubenstein RC, Egan ME, Zeitlin PL. In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR. J Clin Invest 1997; 100:2457-2465.
26. Jiang C, Fang SL, Xiao YF, et al. Partial restoration of cAMP-stimulated CFTR chloride channel activity in DeltaF508 cells by deoxyspergualin. Am J Physiol 1998; 275:C171-C178.
27. Kelley TJ, Al Nakkash L, Cotton CU, Drumm ML. Activation of endogenous deltaF508 cystic fibrosis transmembrane conductance regulator by phosphodiesterase inhibition. J Clin Invest 1996; 98:513-520.
28. Maitra R, Shaw CM, Stanton BA, Hamilton JW. Increased functional cell surface expression of CFTR and DeltaF508-CFTR by the anthracycline doxorubicin. Am J Physiol Cell Physiol 2001; 280:C1031-C1037.
29. Jacobson KA, Guay-Broder C, van Galen PJ, et al. Stimulation by alkylxanthines of chloride efflux in CFPAC-1 cells does not involve A1 adenosine receptors. Biochemistry 1995; 34:9088-9094.
30. Zaman K, McPherson M, Vaughan J, et al. S-nitrosoglutathione increases cystic fibrosis transmembrane regulator maturation. Biochem Biophys Res Commun 2001; 284:65-70.
31. Andersson C, Gaston B, Roomans GM. S-Nitrosoglutathione induces functional DeltaF508-CFTR in airway epithelial cells. Biochem Biophys Res Commun 2002; 297:552-557.
32. Dormer RL, Derand R, McNeilly CM, et al. Correction of delF508-CFTR activity with benzo(c)quinolizinium compounds through facilitation of its processing in cystic fibrosis airway cells. J Cell Sci 2001; 114:4073-4081.
33. Egan ME, Glockner-Pagel J, Ambrose C, et al. Calcium-pump inhibitors induce functional surface expression of Delta F508-CFTR protein in cystic fibrosis epithelial cells. Nat Med 2002; 8:485-492.
34. Egan ME, Pearson M, Weiner SA, et al. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science 2004; 304:600-602. Curcumin, which has a similar mechanism of action to Thapsigargin, also was shown to improve ΔF508-CFTR intracellular trafficking, as well as normalize NPD measurements in ΔF508 CF mice. However, these data remain controversial, because other groups have had difficulty reproducing them.
35. Kelley TJ, Thomas K, Milgram LJ, Drumm ML. In vivo activation of the cystic fibrosis transmembrane conductance regulator mutant deltaF508 in murine nasal epithelium. Proc Natl Acad Sci USA 1997; 94:2604-2608.
36. Fischer H, Fukuda N, Barbry P, et al. Partial restoration of defective chloride conductance in DeltaF508 CF mice by trimethylamine oxide. Am J Physiol Lung Cell Mol Physiol 2001; 281:L52-L57.
37. Zeitlin PL, Diener-West M, Rubenstein RC, et al. Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate. Mol Ther 2002; 6:119-126.
38. Brusilow SW. Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion. Pediatr Res 1991; 29:147-150.
39. Rubenstein RC, Zeitlin PL. Sodium 4-phenylbutyrate downregulates Hsc70: implications for intracellular trafficking of DeltaF508-CFTR. Am J Physiol Cell Physiol 2000; 278:C259-C267.
40. Rubenstein RC, Lyons BM. Sodium 4-phenylbutyrate downregulates HSC70 expression by facilitating mRNA degradation. Am J Physiol Lung Cell Mol Physiol 2001; 281:L43-L51.
41. Choo-Kang LR, Zeitlin PL. Induction of HSP70 promotes DeltaF508 CFTR trafficking. Am J Physiol Lung Cell Mol Physiol 2001; 281:L58-L68.
42. Rubenstein RC, Zeitlin PL. A pilot clinical trial of oral sodium 4-phenylbutyrate (Buphenyl) in deltaF508-homozygous cystic fibrosis patients: partial restoration of nasal epithelial CFTR function. Am J Respir Crit Care Med 1998; 157:484-490.
43. Song Y, Sonawane ND, Salinas D, et al. Evidence against rescue of defective %Dgr;F508-CFTR cellular processing by curcumin in cell culture and mouse models. J Biol Chem 2004. One group's data demonstrating difficulty reproducing the curcumin effect on ΔF508-CFTR trafficking reported in reference 34.
44. Yang H, Shelat AA, Guy RK, et al. Nanomolar affinity small molecule correctors of defective Delta F508-CFTR chloride channel gating. J Biol Chem 2003; 278:35079-35085.
45. Gonzalez JE, Oades K, Leychkis Y, et al. Cell-based assays and instrumentation for screening ion-channel targets. Drug Discov Today 1999; 4:431-439.
46. Logan J, Hiestand D, Daram P, et al. Cystic fibrosis transmembrane conductance regulator mutations that disrupt nucleotide binding. J Clin Invest 1994; 94:228-236.
47. Hwang TC, Wang F, Yang IC, Reenstra WW. Genistein potentiates wild-type and delta F508-CFTR channel activity. Am J Physiol 1997; 273: C988-C998.
48. Illek B, Zhang L, Lewis NC, et al. Defective function of the cystic fibrosis- causing missense mutation G551D is recovered by genistein. Am J Physiol 1999; 277:C833-C839.
49. Urban D, Irwin W, Kirk M, et al. The effect of isolated soy protein on plasma biomarkers in elderly men with elevated serum prostate specific antigen. J Urol 2001; 165:294-300.
50. Galietta LV, Jayaraman S, Verkman AS. Cell-based assay for high-throughput quantitative screening of CFTR chloride transport agonists. Am J Physiol Cell Physiol 2001; 281:C1734-C1742.
51. Caci E, Folli C, Zegarra-Moran O, et al. CFTR activation in human bronchial epithelial cells by novel benzoflavone and benzimidazolone compounds. Am J Physiol Lung Cell Mol Physiol 2003; 285:L180-L188.
52. Ma T, Vetrivel L, Yang H, et al. High-affinity activators of cystic fibrosis transmembrane conductance regulator (CFTR) chloride conductance identified by high-throughput screening. J Biol Chem 2002; 277:37235-37241.
53. Galietta LJ, Springsteel MF, Eda M, et al. Novel CFTR chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds. J Biol Chem 2001; 276: 19723-19728.
54. Sheppard DN, Rich DP, Ostedgaard LS, et al. Mutations in CFTR associated with mild-disease-form Cl- channels with altered pore properties. Nature 1993; 362:160-164.
55. Dalemans W, Barbry P, Champigny G, et al. Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature 1991;354:526-528.
56. Li C, Ramjeesingh M, Reyes E, et al. The cystic fibrosis mutation (delta F508) does not influence the chloride channel activity of CFTR. Nat Genet 1993; 3:311-316.
57. Randak C, Welsh MJ. An intrinsic adenylate kinase activity regulates gating of the ABC transporter CFTR. Cell 2003; 115:837-850.
58. Lim M, McKenzie K, Floyd AD, et al. Modulation of DeltaF508 CFTR trafficking and function with 4-PBA and flavonoids. Am J Respir Cell Mol Biol 2004; 31:351-357.
59. Schwiebert EM, Egan ME, Hwang TH, et al. CFTR regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP. Cell 1995; 81:1063-1073.
60. Reisin IL, Prat AG, Abraham EH, et al. The cystic fibrosis transmembrane conductance regulator is a dual ATP and chloride channel. J Biol Chem 1994; 269:20584-20591.
61. Braunstein GM, Roman RM, Clancy JP, et al. Cystic fibrosis transmembrane conductance regulator facilitates ATP release by stimulating a separate ATP release channel for autocrine control of cell volume regulation. J Biol Chem 2001; 276:6621-6630.
62. Linsdell P, Hanrahan JW. Glutathione permeability of CFTR. Am J Physiol 1998; 275:C323-C326.
63. Choi JY, Muallem D, Kiselyov K, et al. Aberrant CFTR-dependent HCO3-transport in mutations associated with cystic fibrosis. Nature 2001; 410: 94-97.
64. Konstas AA, Koch JP, Tucker SJ, Korbmacher C. Cystic fibrosis transmembrane conductance regulator-dependent up-regulation of Kir1.1 (ROMK) renal K+ channels by the epithelial sodium channel. J Biol Chem 2002; 277:25377-25384.
65. Briel M, Greger R, Kunzelmann K. Cl- transport by cystic fibrosis transmembrane conductance regulator (CFTR) contributes to the inhibition of epithelial Na+ channels (ENaCs) in Xenopus oocytes co-expressing CFTR and ENaC. J Physiol 1998; 508:825-836.
66. Chabot H, Vives MF, Dagenais A, et al. Downregulation of epithelial sodium channel (ENaC) by CFTR co-expressed in Xenopus oocytes is independent of Cl- conductance. J Membr Biol 1999; 169:175-188.
67. Ismailov II, Awayda MS, Jovov B, et al. Regulation of epithelial sodium channels by the cystic fibrosis transmembrane conductance regulator. J Biol Chem 1996; 271:4725-4732.
68. Ji HL, Chalfant ML, Jovov B, et al. The cytosolic termini of the beta- and gamma-ENaC subunits are involved in the functional interactions between cystic fibrosis transmembrane conductance regulator and epithelial sodium channel. J Biol Chem 2000; 275:27947-27956.
69. Jiang Q, Li J, Dubroff R, et al. Epithelial sodium channels regulate cystic fibrosis transmembrane conductance regulator chloride channels in Xenopus oocytes. J Biol Chem 2000; 275:13266-13274.
70. Suaud L, Li J, Jiang Q, et al. Genistein restores functional interactions between Delta F508-CFTR and ENaC in Xenopus oocytes. J Biol Chem 2002; 277:8928-8933.
71. Reddy MM, Light MJ, Quinton PM. Activation of the epithelial Na+ channel (ENaC) requires CFTR Cl- channel function. Nature 1999; 402:301-304.
72. Egan M, Flotte T, Afione S, et al. Defective regulation of outwardly rectifying Cl- channels by protein kinase A corrected by insertion of CFTR. Nature 1992; 358:581-584.
73. Matsui H, Grubb BR, Tarran R, et al. Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 1998; 95:1005-1015.
74. Worlitzsch D, Tarran R, Ulrich M, et al. Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest 2002; 109:317-325.
75. Tarran R, Grubb BR, Parsons D, et al. The CF salt controversy: in vivo observations and therapeutic approaches. Mol Cell 2001; 8:149-158.
76. Mall M, Grubb BR, Harkema JR, et al. Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat Med 2004; 10:487-493. A mouse model that recapitulates most characteristics of CF lung disease, including decreased mucociliary clearance, spontaneous inflammation without bacterial infection, and a predilection to bacterial infection. This is a fascinating model in that these defects result merely from overexpression of an ENaC subunit in the presence of intact murine CFTR, and therefore support the hypothesis that ENaC hyperactivity is critical in the pathophysiology of the CF airway.
77. Mall M, Hipper A, Greger R, Kunzelmann K. Wild type but not deltaF508 CFTR inhibits Na+ conductance when coexpressed in Xenopus oocytes. FEBS Lett 1996; 381:47-52.
78. Yan W, Samaha FF, Ramkumar M, et al. Cystic fibrosis transmembrane conductance regulator differentially regulates human and mouse epithelial sodium channels in Xenopus oocytes. J Biol Chem 2004; 279:23183-23192. Demonstration that CFTR may regulate human and murine ENaC differently. This article also details that a naturally occurring polymorphism of human α-ENaC may also influence these regulatory interactions.
79. Kunzelmann K, Kiser GL, Schreiber R, Riordan JR. Inhibition of epithelial Na+ currents by intracellular domains of the cystic fibrosis transmembrane conductance regulator. FEBS Lett 1997; 400:341-344.
80. Suaud L, Carattino M, Kleyman TR, Rubenstein RC. Genistein improves regulatory interactions between G551 D-cystic fibrosis transmembrane conductance regulator and the epithelial sodium channel in Xenopus oocytes. J Biol Chem 2002; 277:50341-50347.
81. Knowles MR, Clarke LL, Boucher RC. Activation by extracellular nucleotides of chloride secretion in the airway epithelia of patients with cystic fibrosis. N Engl J Med 1991; 325:533-538. ([see comments])
82. Donaldson SH, Lazarowski ER, Picher M, et al. Basal nucleotide levels, release, and metabolism in normal and cystic fibrosis airways. Mol Med 2000; 6:969-982.
83. Watt WC, Lazarowski ER, Boucher RC. Cystic fibrosis transmembrane regulator-independent release of ATP. Its implications for the regulation of P2Y2 receptors in airway epithelia. J Biol Chem 1998; 273:14053-14058.
84. Huang P, Lazarowski ER, Tarran R, et al. Compartmentalized autocrine signaling to cystic fibrosis transmembrane conductance regulator at the apical membrane of airway epithelial cells. Proc Natl Acad Sci USA 2001; 98: 14120-14125.
85. Kunzelmann K, Schreiber R, Boucherot A. Mechanisms of the inhibition of epithelial Na(+) channels by CFTR and purinergic stimulation. Kidney Int 2001; 60:455-461.
86. Devor DC, Pilewski JM. UTP inhibits Na+ absorption in wild-type and DeltaF508 CFTR-expressing human bronchial epithelia. Am J Physiol 1999; 276:C827-C837.
87. Tarran R, Loewen ME, Paradiso AM, et al. Regulation of murine airway surface liquid volume by CFTR and Ca2+-activated Cl- conductances. J Gen Physiol 2002; 120:407-418.
88. Paradiso AM, Ribeiro CM, Boucher RC. Polarized signaling via purinoceptors in normal and cystic fibrosis airway epithelia. J Gen Physiol 2001; 117:53-67.
89. Stutts MJ, Fitz JG, Paradiso AM, Boucher RC. Multiple modes of regulation of airway epithelial chloride secretion by extracellular ATP. Am J Physiol 1994; 267:C1442-C1451.
90. Donaldson SH, Picher M, Boucher RC. Secreted and cell-associated adenylate kinase and nucleoside diphosphokinase contribute to extracellular nucleotide metabolism on human airway surfaces. Am J Respir Cell MoI Biol 2002; 26:209-215.
91. Picher M, Burch LH, Hirsh AJ, et al. Ecto 5′-nucleotidase and nonspecific alkaline phosphatase. Two AMP-hydrolyzing ectoenzymes with distinct roles in human airways. J Biol Chem 2003; 278:13468-13479.
92. Lazarowski ER, Boucher RC, Harden TK. Constitutive release of ATP and evidence for major contribution of ecto-nucleotide pyrophosphatase and nucleoside diphosphokinase to extracellular nucleotide concentrations. J Biol Chem 2000; 275:31061-31068.
93. Lazarowski ER, Homolya L, Boucher RC, Harden TK. Identification of an ecto-nucleoside diphosphokinase and its contribution to interconversion of P2 receptor agonists. J Biol Chem 1997; 272:20402-20407.
94. Picher M, Boucher RC. Human airway ecto-adenylate kinase. A mechanism to propagate ATP signaling on airway surfaces. J Biol Chem 2003; 278: 11256-11264.
95. Picher M, Burch LH, Boucher RC. Metabolism of P2 receptor agonists in human airways: implications for mucociliary clearance and cystic fibrosis. J Biol Chem 2004; 279:20234-20241.
96. Bennett WD, Zeman KL, Foy C, et al. Effect of aerosolized uridine 5′-triphosphate on mucociliary clearance in mild chronic bronchitis. Am J Respir Crit Care Med 2001; 164:302-306.
97. Noone PG, Bennett WD, Regnis JA, et al. Effect of aerosolized uridine-5′-triphosphate on airway clearance with cough in patients with primary ciliary dyskinesia. Am J Respir Crit Care Med 1999; 160:144-149.
98. Noone PG, Hamblett N, Accurso F, et al. Safety of aerosolized INS 365 in patients with mild to moderate cystic fibrosis: results of a phase I multi-center study. Pediatr Pulmonol 2001; 32:122-128.
99. Yerxa BR, Sabater JR, Davis CW, et al. Pharmacology of INS37217 [P(1)-(uridine 5′)-P(4)- (2′-deoxycytidine 5′)tetraphosphate, tetrasodium salt], a next-generation P2Y(2) receptor agonist for the treatment of cystic fibrosis. J Pharmacol Exp Ther 2002; 302:871-880.
100. Kellerman D, Evans R, Mathews D, Shaffer C. Inhaled P2Y2 receptor agonists as a treatment for patients with cystic fibrosis lung disease. Adv Drug Deliv Rev 2002; 54:1463-1474.
101. Grubb BR, Vick RN, Boucher RC. Hyperabsorption of Na+ and raised Ca(2+)-mediated Cl- secretion in nasal epithelia of CF mice. Am J Physiol 1994; 266:C1478-C1483.
102. Cloutier MM, Guernsey L, Sha'afi RI. Duramycin increases intracellular calcium in airway epithelium. Membr Biochem 1993; 10:107-118.
103. Cloutier MM, Guernsey L, Mattes P, Koeppen B. Duramycin enhances chloride secretion in airway epithelium. Am J Physiol 1990; 259:C450-C454.
104. Zeitlin PL, Boyle MP, Guggino WB, Molina L. A phase I trial of intranasal Moli1901 for cystic fibrosis. Chest 2004; 125:143-149. A pilot, proof of concept trial suggesting that Duramycin may improve chloride transport in the CF airway.
105. Murray CB, Morales MM, Flotte TR, et al. CIC-2: a developmentally dependent chloride channel expressed in the fetal lung and downregulated after birth. Am J Respir Cell Mol Biol 1995; 12:597-604.
106. Zdebik AA, Cuffe JE, Bertog M, et al. Additional disruption of the CIC-2 Cl(-) channel does not exacerbate the cystic fibrosis phenotype of cystic fibrosis transmembrane conductance regulator mouse models. J Biol Chem 2004; 279:22276-22283. Given that CIC-2 has been hypothesized as an apical chloride channel that may be able to compensate for the absence of CFTR, these data suggesting that additional knockout of CIC-2 does not worsen, and may even benefit the phenotype of the CF mouse model are quite provocative. These data, however, may not apply to the CF airway given the relative lack of airway disease in the CF mouse.
107. Cuppoletti J, Malinowska DH, Tewari KP, et al. SPI-0211 activates T84 cell Cl- transport and recombinant human CIC-2 Cl- currents. Am J Physiol Cell Physiol 2004; 287:C1173-1183. Report of a novel activator of CIC-2. Such activation of CIC-2 may be more useful in the airway, and reference 107 does not really address the role of CIC-2 in the CF mouse airway, because the primary disease of the CF mouse is in the intestine.
108. Gyomorey K, Yeger H, Ackerley C, et al. Expression of the chloride channel CIC-2 in the murine small intestine epithelium. Am J Physiol Cell Physiol 2000; 279:C1787-C1794.
109. Mohammad-Panah R, Gyomorey K, Rommens J, et al. CIC-2 contributes to native chloride secretion by a human intestinal cell line, Caco-2. J Biol Chem 2001; 276:8306-8313.
110. Schwiebert EM, Cid-Soto LP, Stafford D, et al. Analysis of CIC-2 channels as an alternative pathway for chloride conduction in cystic fibrosis airway cells. Proc Natl Acad Sci USA 1998; 95:3879-3884.
111. Cuppoletti J, Tewari KP, Sherry AM, et al. CIC-2 Cl- channels in human lung epithelia: activation by arachidonic acid, amidation, and acid-activated omeprazole. Am J Physiol Cell Physiol 2001; 281:C46-C54.
112. Knowles MR, Church NL, Waltner WE, et al. A pilot study of aerosolized amiloride for the treatment of lung disease in cystic fibrosis. N Engl J Med 1990; 322:1189-1194.
113. Noone PG, Regnis JA, Liu X, et al. Airway deposition and clearance and systemic pharmacokinetics of amiloride following aerosolization with an ultrasonic nebulizer to normal airways. Chest 1997; 112:1283-1290.
114. Olivier KN, Bennett WD, Hohneker KW, et al. Acute safety and effects on mucociliary clearance of aerosolized uridine 5′-triphosphate +/- amiloride in normal human adults. Am J Respir Crit Care Med 1996; 154:217-223.
115. Hofmann T, Stutts MJ, Ziersch A, et al. Effects of topically delivered benzamil and amiloride on nasal potential difference in cystic fibrosis. Am J Respir Crit Care Med 1998; 157:1844-1849.
116. Vallet V, Pfister C, Loffing J, Rossier BC. Cell-surface expression of the channel activating protease xCAP-1 is required for activation of ENaC in the Xenopus oocyte. J Am Soc Nephrol 2002; 13:588-594.
117. Vallet V, Chraibi A, Gaeggeler HP, et al. An epithelial serine protease activates the amiloride-sensitive sodium channel. Nature 1997; 389: 607-610.
118. Vuagniaux G, Vallet V, Jaeger NF, et al. Synergistic activation of ENaC by three membrane-bound channel-activating serine proteases (mCAP1, mCAP2, and mCAP3) and serum- and glucocorticoid-regulated kinase (Sgk1) in Xenopus oocytes. J Gen Physiol 2002; 120:191-201.
119. Vuagniaux G, Vallet V, Jaeger NF, et al. Activation of the amiloride-sensitive epithelial sodium channel by the serine protease mCAP1 expressed in a mouse cortical collecting duct cell line. J Am Soc Nephrol 2000; 11: 828-834.
120. Adachi M, Kitamura K, Miyoshi T, et al. Activation of epithelial sodium channels by prostasin in Xenopus oocytes. J Am Soc Nephrol 2001; 12: 1114-1121.
121. Hughey RP, Mueller GM, Bruns JB, et al. Maturation of the epithelial Na+ channel involves proteolytic processing of the alpha- and gamma-subunits. J Biol Chem 2003; 278:37073-37082.
122. Hughey RP, Bruns JB, Kinlough CL, et al. Epithelial sodium channels are activated by furin-dependent proteolysis. J Biol Chem 2004; 279:18111-18114. See [121]
123. Caldwell RA, Boucher RC, Stutts MJ. Serine protease activation of near-silent epithelial Na+ channels. Am J Physiol Cell Physiol 2004; 286: C190-C194. These provocative data suggest that proteases that are present in the CF airway may lead to further activation of ENaC. This may, in turn, worsen the hyperabsorption of sodium in the CF airway.
124. Donaldson SH, Hirsh A, Li DC, et al. Regulation of the epithelial sodium channel by serine proteases in human airways. J Biol Chem 2002; 277: 8338-8345.
125. Tong Z, Illek B, Bhagwandin VJ, et al. Prostasin, a membrane-anchored serine peptidase, regulates sodium currents in JME/CF15 cells, a cystic fibrosis airway epithelial cell line. Am J Physiol Lung Cell Mol Physiol 2004; 287: L928-L935.
126. Bridges RJ, Newton BB, Pilewski JM, etal. Na+ transport in normal and CF human bronchial epithelial cells is inhibited by BAY 39-9437. Am J Physiol Lung Cell Mol Physiol 2001; 281:L16-L23.