Too much salt, too little soda: cystic fibrosis

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Author:
QUINTON Paul M.()
Journal Title:
ACTA PHYSIOLOGICA SINICA
Issue:
Volume 59, Issue 04, 2007
DOI:
Key Word:
sweat glands;pancreas;airways;ion transport;mucus;cystic fibrosis transmembrane conductance regulator;chloride;bicarbonate;genetic disease

Abstract: Cystic fibrosis (CF) of the pancreas is the most widely Accepted name of the most common fatal inherited single gene defect disease among Caucasians. Its incidence among other races is thought to be significantly less, but mutations in the gene have been reported in most, if not all, major populations. This review is intended to give general concepts of the molecular as well as physiological basis of the pathology that develops in the disease. First, an overview of the organ pathology and genetics is presented, followed by the molecular structure of the gene product (cystic fibrosis transmembrane conductance regulator, CFTR), its properties, functions, and controls as currently understood. Second, since mutations appear to be expressed primarily as a defect in electrolyte transport, effects and mechanisms of pathology are presented for two characteristically affected organs where the etiology is best described: the sweat gland, which excretes far too much NaCl ("salt") and the pancreas, which excretes far too little HCO3- ("soda"). Unfortunately,morbidity and mortality in CF develop principally from refractory airway infections, the basis of which remains controversial.Consequently, we conclude by considering possible mechanisms by which defects in anion transport might predispose the CF lung to chronic infections.

  • [1]Fink RJ,Doershuk CF,Tucker AS,Stern RC,Boat TF,Matthews LW.Pulmonary function and morbidity in 40 adult patients with cystic fibrosis.Chest 1978; 74:643-647.
  • [2]Kristidis P,Bozon D,Corey M,Markiewicz D,Rommens J,Tsui LC,Durie P.Genetic determination of exocrine pancreatic function in cystic fibrosis.Am J Hum Genet 1992; 50:1178-1184.
  • [3]Di Sant'Agnese PA,Powell GF.The eccrine sweat defect in cystic fibrosis of the pancreas (mucoviscidosis).Ann NY Acad Sci 1962; 93:555-599.
  • [4]Shwachman H,Antonowicz I.Sweat test in cystic fibrosis.Ann NY Aca Sci 1962; 93:600.
  • [5]Munck A,Gerardin M,Alberti C,Ajzenman C,Lebourgeois M,Aigrain Y,Navarro J.Clinical outcome of cystic fibrosis presenting with or without meconium ileus:a matched cohort study.J Pediatr Surg 2006; 41:1556-1560.
  • [6]Wiesmann UN,Boat TF,Di Sant'Agnese PA.Flow-rates and electrolytes in minor-salivary-gland saliva in normal subjects and patients with cystic fibrosis.Lancet 1972; 2:510-512.
  • [7]Warwick WJ,Bernard B,Meskin LH.The involvement of the labial mucous salivary gland in patients with cystic fibrosis.Pediatrics 1964; 34:621-628.
  • [8]Joo NS,Irokawa T,Robbins RC,Wine JJ.Hyposecretion,not hyperabsorption,is the basic defect of cystic fibrosis airway glands.J Biol Chem 2006; 281:7392-7398.
  • [9]Farber S.Pancreatic function and disease in early life.V.Pathological changes associated with pancreatic insufficiency in early life.Arch Pathol 1944; 37:238-250.
  • [10]Pratha VS,Hogan DL,Martensson BA,Bernard J,Zhou R,Isenberg JI.Identification of transport abnormalities in duodenal mucosa and duodenal enterocytes from patients with cystic fibrosis.Gastroenterology 2000; 118:1051-1060.
  • [11]Russo MA,Hogenauer C,Coates SW Jr,Santa Ana CA,Porter JL,Rosenblatt RL,Emmett M,Fordtran JS.Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect.J Clin Invest 2003;112:118-125.
  • [12]Esterly JR,Oppenheimer EH.Observations in cystic fibrosis of the pancreas.I.The gallbladder.Bull Johns Hopkins Hosp 1962; 110:247-255.
  • [13]Blanc WA,Di Sant'Agnese PA.A distinctive type of biliary cirrhosis of the liver associated with cystic fibrosis of the pancreas.Pediatrics 1956; 18:387-409.
  • [14]Lindblad A,Hultcrantz R,Strandvik B.Bile-duct destruction and collagen deposition:a prominent ultrastructural feature of the liver in cystic fibrosis.Hepatology 1992; 16:372-381.
  • [15]Kopito LE,Kosasky HJ,Shwachman H.Water and electrolytes in cervical mucus from patients with cystic fibrosis.Fertil Steril 1973; 24:512-516.
  • [16]Kaplan E,Shwachman H,Perlmutter AD,Rule A,Khaw KT,Holsclaw DS.Reproductive failure in males with cystic fibrosis.N Engl J Med 1968; 279:65-69.
  • [17]Rule AH,Kopito L,Shwachman H.Chemical analysis of ejaculates from patients with cystic fibrosis.Fertil Steril 1970;21:515-520.
  • [18]Holsclaw DS,Perlmutter AD,Jockin H,Shwachman H.Genital abnormalities in male patients with cystic fibrosis.J Urol 1971;106:568-574.
  • [19]Zuelzer WW,Newton WA.The pathogenesis of fibrocystic disease of the pancreas.A study of 36 cases with special reference to the pulmonary lesions.Pediatrics 1949; 4:53-69.
  • [20]Bodian M.Fibrocystic Disease of the Pancreas:A Congenital Disorder of Mucus Production-Mucosis.New York:Grune and Stratton,Inc.,1953,1-244.
  • [21]Gugler E,Pallavicini CJ,Swerdlow H,Di Sant'Agnese PA.The role of calcium in submaxillary saliva of patients with cystic fibrosis.J Pediatr 1967; 71:585-588.
  • [22]Burgel PR,Montani D,Danel C,Dusser DJ,Nadel JA.A morphometric study of mucins and small airway plugging in cystic fibrosis.Thorax 2007; 62:153-161.
  • [23]Andersen DH.Cystic fibrosis of the pancreas and its relation to celiac disease.Am J Dis Child 1938; 56:344-399.
  • [24]Andersen DH,Hodges RG.Celiac syndrome.V.Genetics of cystic fibrosis of the pancreas with a consideration of the etiology.Am J Dis Child 1946; 72:62-80.
  • [25]Statistics.Cystic Fibrosis Statistics.http://personalnbnetnbca/normap/cfstatshtm
  • [26]Kerem B,Rommens JM,Buchanan JA,Markiewicz D,Cox TK,Chakravarti A,Buchwald M,Tsui LC.Identification of the cystic fibrosis gene:genetic analysis.Science 1989; 245:1073-1080.
  • [27]Riordan JR,Rommens JM,Kerem B,Alon N,Rozmahel R,Grzelczak Z,Zielenski J,Lok S,Plavsic N,Chou JL,et al.Identification of the cystic fibrosis gene:cloning and characterization of complementary DNA.Science 1989; 245:1066-1073.
  • [28]Rommens JM,Iannuzzi MC,Kerem B,Drumm ML,Melmer G,Dean M,Rozmahel R,Cole JL,Kennedy D,Hidaka N,Collins FS,et al.Identification of the cystic fibrosis gene:chromosome walking and jumping.Science 1989; 245:1059-1065.
  • [29]Palomaki GE,FitzSimmons SC,Haddow JE.Clinical sensitivity of prenatal screening for cystic fibrosis via CFTR carrier testing in a United States panethnic population.Genet Med 2004;6:405-414.
  • [30]Database.Cystic Fibrosis Mutation Database.In:http://www.genet.sickkids.on.ca/cftr/
  • [31]Wang W,Okayama H,Shirato K.Genotypes of cystic fibrosis (CF) reported in the world and polymorphisms of cystic fibrosis transmembrane conductance regulator (CFTR) gene in Japanese.Nippon Rinsho 1996; 54:525-532.
  • [32]Lee JH,Choi JH,Namkung W,Hanrahan JW,Chang J,Song SY,Park SW,Kim DS,Yoon JH,Suh Y,Jang IJ,Nam JH,Kim SJ,Cho MO,Lee JE,Kim KH,Lee MG.A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases.Hum Mol Genet 2003; 12:2321-2332.
  • [33]Nam MH,Hijikata M,Tuan le A,Lien LT,Shojima J,Horie T,Nakata K,Matsushita I,Ohashi J,Tokunaga K,Keicho N.Variations of the CFTR gene in the Hanoi-Vietnamese.Am J Med Genet A 2005; 136:249-253.
  • [34]NgiamNS,Chong SS,Shek LP,Goh DL,Ong KC,Chng SY,Yeo GH,Goh DY.Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease:A pilot study.J Cyst Fibros 2006; 5:159-164.
  • [35]Zilfalil BA,Sarina S,Liza-Sharmini AT,Oldfield NJ,Stenhouse SA.Detection of F508del mutation in cystic fibrosis transmembrane conductance regulator gene mutation among Malays.Singapore Med J 2006; 47:129-133.
  • [36]Quinton PM.Chloride impermeability in cystic fibrosis.Nature 1983; 301:421-422.
  • [37]Sheppard DN,Welsh MJ.Structure and function of the CFTR chloride channel.Physiol Rev 1999; 79:S23-S45.
  • [38]Welsh MJ,Smith AE.Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis.Cell 1993; 73:1251-1254.
  • [39]Rowe SM,Miller S,Sorscher EJ.Cystic fibrosis.N Engl J Med 2005; 352:1992-2001.
  • [40]Zielenski J.Genotype and phenotype in cystic fibrosis.Respiration 2000; 67(2):117-133.
  • [41]Ahmed N,Corey M,Forstner G,Zielenski J,Tsui LC,Ellis L,Tullis E,Durie P.Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas.Gut 2003; 52:1159-1164.
  • [42]Rowntree RK,Harris A.The phenotypic consequences of CFTR mutations.Ann Hum Genet 2003; 67:471-485.
  • [43]Gray MA,Harris A,Coleman L,Greenwell JR,Argent BE.Two types of chloride channel on duct cells cultured from human fetal pancreas.Am J Physiol 1989; 257:C240-C251.
  • [44]Berger HA,Anderson MP,Gregory RJ,Thompson S,Howard PW,Maurer RA,Mulligan R,Smith AE,Welsh MJ.Identification and regulation of the cystic fibrosis transmembrane conductance regulator-generated chloride channel.J Clin Invest 1991; 88:1422-1431.
  • [45]Linsdell P,Tabcharani JA,Rommens JM,Hou YX,Chang XB,Tsui LC,Riordan JR,Hanrahan JW.Permeability of wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride channels to polyatomic anions.J Gen Physiol 1997;110:355-364.
  • [46]Greger R,Mall M,Bleich M,Ecke D,Warth R,Riedemann N,Kunzelmann K.Regulation of epithelial ion channels by the cystic fibrosis transmembrane conductance regulator.J Mol Med 1996; 74:527-534.
  • [47]Kunzelmann K.CFTR:interacting with everything? News Physiol Sci 2001; 16:167-170.
  • [48]Sato K,Sato F.Defective beta adrenergic response of cystic fibrosis sweat glands in vivo and in vitro.J Clin Invest 1984; 73:1763-1771.
  • [49]Sato K,Sato F.Variable reduction in beta-adrenergic sweat secretion in cystic fibrosis heterozygotes.J Lab Clin Med 1988;111:511-518.
  • [50]Hitchin BW,Dobson PR,Brown BL,Hardcastle J,Hardcastle PT,Taylor CJ.Measurement of intracellular mediators in enterocytes isolated from jejunal biopsy specimens of control and cystic fibrosis patients.Gut 1991; 32:893-899.
  • [51]Cheng SH,Rich DP,Marshall J,Gregory RJ,Welsh MJ,Smith AE.Phosphorylation of the R domain by cAMP-dependent protein kinase regulates the CFTR chloride channel.Cell 1991;66:1027-1036.
  • [52]Quinton PM,Reddy MM.Regulation of absorption by phosphorylation of CFTR.Jpn J Physiol 1994; 44 (Suppl 2):S207-S213.
  • [53]Li C,Ramjeesingh M,Wang W,Garami E,Hewryk M,Lee D,Rommens JM,Galley K,Bear CE.ATPase activity of the cystic fibrosis transmembrane conductance regulator.J Biol Chem 1996; 271:28463-28468.
  • [54]Gadsby DC,Dousmanis AG,Nairn AC.ATP hydrolysis cycles and the gating of CFTR Cl-channels.Acta Physiol Scand (Suppl) 1998; 643:247-256.
  • [55]Quinton PM.Effects of some ion transport inhibitors on secretion and reabsorption in intact and perfused single human sweat glands.Pflugers Arch 1981; 391:309-313.
  • [56]Schwencke C,Yamamoto M,Okumura S,Toya Y,Kim SJ,Ishikawa Y.Compartmentation of cyclic adenosine 3',5'-monophosphate signaling in caveolae.Mol Endocrinol 1999; 13:1061-1070.
  • [57]Ostrom RS,Violin JD,Coleman S,Insel PA.Selective enhancement of beta-adrenergic receptor signaling by overexpression of adenylyl cyclase type 6:colocalization of receptor and adenylyl cyclase in caveolae of cardiac myocytes.Mol Pharmacol 2000; 57(5):1075-1079.
  • [58]Rich DP,Berger HA,Cheng SH,Travis SM,Saxena M,Smith AE,Welsh MJ.Regulation of the cystic fibrosis transmembrane conductance regulator Cl channel by negative charge in the R domain.J Biol Chem 1993; 268:20259-20267.
  • [59]Gadsby DC,Nairn AC.Regulation of CFTR channel gating.Trends Biochem Sci 1994; 19:513-518.
  • [60]Dahan D,Evagelidis A,Hanrahan JW,Hinkson DA,Jia Y,Luo J,Zhu T.Regulation of the CFTR channel by phosphorylation.Pflugers Arch 2001; 443 (Suppl 1):S92-S96.
  • [61]Chang XB,Tabcharani JA,Hou YX,Jensen TJ,Kartner N,Alon N,Hanrahan JW,Riordan JR.Protein kinase A (PKA) still activates CFTR chloride channel after mutagenesis of all 10 PKA consensus phosphorylation sites.J Biol Chem 1993;268:11304-11311.
  • [62]Seibert FS,Chang XB,Aleksandrov AA,Clarke DM,Hanrahan JW,Riordan JR.Influence of phosphorylation by protein kinase A on CFTR at the cell surface and endoplasmic reticulum.Biochim Biophys Acta 1999; 1461:275-283.
  • [63]Jia Y,Mathews CJ,Hanrahan JW.Phosphorylation by protein kinase C is required for acute activation of cystic fibrosis transmembrane conductance regulator by protein kinase A.J Biol Chem 1997; 272:4978-4984.
  • [64]Liedtke CM,Cole TS.Antisense oligonucleotide to PKCepsilon alters cAMP-dependent stimulation of CFTR in Calu-3 cells.Am J Physiol 1998; 275:C1357-C1364.
  • [65]Middleton LM,Harvey RD.PKC regulation of cardiac CFTR Cl-channel function in guinea pig ventricular myocytes.Am J Physiol 1998; 275:C293-C302.
  • [66]Bajnath RB,Groot JA,De Jonge HR,Kansen M,Bijman J.Synergistic activation of non-rectifying small-conductance chloride channels by forskolin and phorbol esters in cell-attached patches of the human colon carcinoma cell line HT-29cl.19A.Pflugers Arch 1993; 425:100-108.
  • [67]Tabcharani JA,Chang XB,Riordan JR,Hanrahan JW.Phosphorylation-regulated Cl-channel in CHO cells stably expressing the cystic fibrosis gene.Nature 1991; 352:628-631.
  • [68]Button B,Reuss L,Altenberg GA.PKC-mediated stimulation of amphibian CFTR depends on a single phosphorylation consensus site.insertion of this site confers PKC sensitivity to human CFTR.J Gen Physiol 2001; 117:457-468.
  • [69]Vaandrager AB,Ehlert EM,Jarchau T,Lohmann SM,de Jonge HR.N-terminal myristoylation is required for membrane localization of cGMP-dependent protein kinase type Ⅱ.J Biol Chem 1996; 271:7025-7029.
  • [70]Reddy MM,Quinton PM.Functional interaction of CFTR and ENaC in sweat glands.Pflugers Arch 2003; 445:499-503.
  • [71]Vaandrager AB,Smolenski A,Tilly BC,Houtsmuller AB,Ehlert EM,Bot AG,Edixhoven M,Boomaars WE,Lohmann SM,de Jonge HR.Membrane targeting of cGMP-dependent protein kinase is required for cystic fibrosis transmembrane conductance regulator Cl-channel activation.Proc Nad Acad Sci USA 1998; 95:1466-1471.
  • [72]Csanady L,Chan KW,Angel BB,Nairn AC,Gadsby DC.Negative regulation of CFTR chloride channel gating through R-domain serine 768.Ped Pulmon 1998; 17:205.
  • [73]Travis SM,Berger HA,Welsh MJ.Protein phosphatase 2C dephosphorylates and inactivates cystic fibrosis transmembrane conductance regulator.Proc Natl Acad Sci USA 1997; 94:11055-11060.
  • [74]Nairn AC,Qin J,Chait BT,Gadsby DC.Indentification of sites in the R domain of CFTR phosphorylated by cAMP-dependent protein kinase and dephosphorylated by protein phosphatase 2A and 2C.Ped Pulmon 1996(Suppl 13):21.
  • [75]Reddy MM,Quinton PM.Deactivation of CFTR-Cl conductance by endogenous phosphatases in the native sweat duct.Am J Physiol 1996; 270:C474-C480.
  • [76]Reddy MM,Quinton PM.Cytosolic potassium controls CFTR deactivation in human sweat duct.Am J Physiol Cell Physiol 2006; 291:C122-C129.
  • [77]Zhu T,Dahan D,Evagelidis A,Zheng S,Luo J,Hanrahan JW.Association of cystic fibrosis transmembrane conductance regulator and protein phosphatase 2C.J Biol Chem 1999; 274:29102-29107.
  • [78]Fischer H,Machen TE.The tyrosine kinase p60c-src regulates the fast gate of the cystic fibrosis transmembrane conductance regulator chloride channel.Biophys J 1996; 71:3073-3082.
  • [79]Nguyen TD,Canada AT,Heintz GG,Gettys TW,Cohn JA.Stimulation of secretion by the T84 colonic epithelial cell line with dietary flavonols.Biochem Pharmacol 1991; 41:1879-1886.
  • [80]Sears CL,Firoozmand F,Mellander A,Chambers FG,Eromar IG,Bot AG,Scholte B,De Jonge HR,Donowitz M.Genistein and tyrphostin 47 stimulate CFTR-mediated Cl-secretion in T84 cell monolayers.Am J Physiol 1995; 269:G874-G882.
  • [81]French PJ,Bijman J,Bot AG,Boomaars WE,Scholte BJ,de Jonge HR.Genistein activates CFTR Cl-channels via a tyrosine kinase-and protein phosphatase-independent mechanism.Am J Physiol 1997; 273:C747-C753.
  • [82]Wang F,Zeltwanger S,Yang IC,Nairn AC,Hwang TC.Actions of genistein on cystic fibrosis transmembrane conductance regulator channel gating.Evidence for two binding sites with opposite effects.J Gen Physiol 1998; 111:477-490.
  • [83]Bulteau-Pignoux L,Derand R,Metaye T,Joffre M,Becq F.Genistein modifies the activation kinetics and magnitude of phosphorylated wild-type and G551D-CFTR chloride currents.J Membr Biol 2002; 188:175-182.
  • [84]Schultz BD,Singh AK,Devor DC,Bridges RJ.Pharmacology of CFTR chloride channel activity.Physiol Rev 1999; 79:S109-S144.
  • [85]Berger AL,Randak CO,Ostedgaard LS,Karp PH,Vermeer DW,Welsh MJ.Curcumin stimulates cystic fibrosis transmembrane conductance regulator Cl-channel activity.J Biol Chem 2005;280:5221-5226.
  • [86]Lansdell KA,Cai Z,Kidd JF,Sheppard DN.Two mechanisms of genistein inhibition of cystic fibrosis transmembrane conductance regulator Cl-channels expressed in murine cell line.J Physiol 2000; 524 (Pt 2):317-330.
  • [87]Moran O,Zegarra-Moran O.A quantitative description of the activation and inhibition of CFTR by potentiators:Genistein.FEBS Lett 2005; 579:3979-3983.
  • [88]Linsdell P,Hanrahan JW.Flickery block of single CFTR chloride channels by intracellular anions and osmolytes.Am J Physiol 1996; 271:C628-C634.
  • [89]Quinton PM,Reddy MM.Control of CFTR chloride conductance by ATP levels through non-hydrolytic binding.Nature 1992; 360:79-81.
  • [90]Bell CL,Quinton PM.Regulation of CFTR Cl-conductance in secretion by cellular energy levels.Am J Physiol 1993; 264:C925-C931.
  • [91]Raj D,Langford M,Krueger S,Shelton M,Welbourne T.Regulatory responses to an oral D-glutamate load:formation of D-pyrrolidone carboxylic acid in humans.Am J Physiol Endocrinol Metab 2001; 280:E214-E220.
  • [92]Dall'Asta V,Bussolati O,Sala R,Parolari A,Alamanni F,Biglioli P,Gazzola GC.Amino acids are compatible osmolytes for volume recovery after hypertonic shrinkage in vascular endothelial cells.Am J Physiol 1999; 276:C865-C872.
  • [93]Reddy MM,Quinton PM.Selective activation of cystic fibrosis transmembrane conductance regulator Cl-and HCO3-conductances.J Pancr (Online) 2001; 2:212-218.
  • [94]Reddy MM,Quinton PM.Control of dynamic CFTR selectivity by glutamate and ATP in epithelial cells.Nature 2003;423:756-760.
  • [95]Egan ME,Pearson M,Weiner SA,Rajendran V,Rubin D,Glockner-Pagel J,Canny S,Du K,Lukacs GL,Caplan MJ.Curcumin,a major constituent of turmeric,corrects cystic fibrosis defects.Science 2004; 304:600-602.
  • [96]Mall M,Kunzelmann K.Correction of the CF defect by curcumin:hypes and disappointments.Bioessays 2005; 27:9-13.
  • [97]Seidler U,Blumenstein I,Kretz A,Viellard-Baron D,Rossmann H,Colledge WH,Evans M,Ratcliff R,Gregor M.A functional CFTR protein is required for mouse intestinal cAMP-,cGMP-and Ca2+-dependent HCO3-secretion.J Physiol 1997; 505 (Pt 2):411-423.
  • [98]Martin LC,Hickman ME,Curtis CM,MacVinish LJ,Cuthbert AW.Electrogenic bicarbonate secretion in mouse gallbladder.Am J Physiol 1998; 274:G1045-G1052.
  • [99]Ianowski JP,Choi JY,Wine JJ,Hanrahan JW.Mucus secretion by single tracheal submucosal glands from normal and CFTR knock-out mice.J Physiol 2007; 580(Pt 1):7-8.
  • [100]Wu JV,Krouse ME,Wine JJ.Acinar origin of CFTR-dependent airway submucosal gland fluid secretion.Am J Physiol Lung Cell Mol Physiol 2007; 292:L304-L311.
  • [101]Choi JY,Joo NS,Krouse ME,Wu JV,Robbins RC,Ianowski JP,Hanrahan JW,Wine JJ.VIP and carbachol cause synergistic airway gland secretion that is lost in cystic fibrosis.J Clin Invest (In Press).
  • [102]Jenkinson DM,Mabon RM,Manson W.Sweat proteins.Br J Dermatol 1974; 90:175-181.
  • [103]Jirka M,Kotas J.The occurrence of mucoproteins in human sweat.Clinica Chimica Acta 1957; 2:292-296.
  • [104]Sato K.The physiology,pharmacology,and biochemistry of the eccrine sweat gland.Rev Physiol Biochem Pharmacol 1977;79:51-131.
  • [105]Quinton PM.Structure and Function of Eccrine Sweat Glands in Humans.In:Antiperspirants and Deodorants.Laden K,Felger CB.eds.New York and Basel:Marcel Dekker,Inc.,1988,57-82.
  • [106]Prompt CA,Quinton PM.Functions of calcium in sweat secretion.Nature 1978; 272:171-172.
  • [107]Kidd JF,Thorn P.Intracellular Ca2+ and Cl-channel activation in secretory cells.Annu Rev Physiol 2000; 62:493-513.
  • [108]Silva P,Stoff J,Field M,Fine L,Forrest JN,Epstein FH.Mechanism of active chloride secretion by shark rectal gland:role of Na-K-ATPase in chloride transport.Am J Physiol 1977;233(4):F298-F306.
  • [109]Harper S,Quinton PM.Adrenergic and cholinergic stimulation of CF sweat glands.In:Cystic Fibrosis:Horizons Proceedings of the 9th International Cystic Fibrosis Congress.1st ed.Lawson D.ed.Brighton,England:John Wiley & Sons,1984,178.
  • [110]Bijman J,Quinton PM.Influence of abnormal Cl-impermeability on sweating in cystic fibrosis.Am J Physiol 1984; 247:C3-C9.
  • [111]Cohn JA,Melhus O,Page LJ,Dittrich KL,Vigna SR.CFTR:development of high-affinity antibodies and localization in sweat gland.Biochem Biophys Res Commun 1991; 181:36-43.
  • [112]Kartner N,Augustinas O,Jensen TJ,Naismith AL,Riordan JR.Mislocalization of delta F508 CFTR in cystic fibrosis sweat gland.Nat Genet 1992; 1:321-327.
  • [113]Quinton PM,Tormey JM.Localization of Na/K-ATPase sites in the secretory and reabsorptive epithelia of perfused eccrine sweat glands:a question to the role of the enzyme in secretion.J Membr Biol 1976; 29 383-399.
  • [114]Conn JW.Electrolyte composition of sweat.Arch Intern Med 1949; 83:416-428.
  • [115]Lobeck CC,McSherry N.Response of sweat electrolyte concentrations to 9 alpha-fluorohydrocortisone in patients with cystic fibrosis and their families.J Pediatr 1963; 62(3):393-398.
  • [116]Reddy MM,Quinton PM.cAMP activation of CF-affected Cl-conductance in both cell membranes of an absorptive epithelium.J Membr Biol 1992; 130:49-62.
  • [117]Quinton PM,Bijman J.Higher bioelectric potentials due to decreased chloride absorption in the sweat glands of patients with cystic fibrosis.N Engl J Med 1983; 308:1185-1189.
  • [118]Ballestero Y,Hemandez MI,Rojo P,Manzanares J,Nebreda V,Carbajosa H,Infante E,Baro M.Hyponatremic dehydration as a presentation of cystic fibrosis.Pediatr Emerg Care 2006; 22:725-727.
  • [119]Di Sant'Agnese PE,Andersen DH.Celiac syndrome.Am J Dis Child 1946; 72:17-61.
  • [120]Farber S.Some organic digestive disturbances in early life.J Mich State Med Soc1945; 44:587-594.
  • [121]Oppenheimer EH,Esterly JR.Pathology of cystic fibrosis review of the literature and comparison with 146 autopsied cases.Perspect Pediatr Pathol 1975; 2:241-278.
  • [122]Marcus MS,Sondel SA,Farrell PM,Laxova A,Carey PM,Langhough R,Mischler EH.Nutritional status of infants with cystic fibrosis associated with early diagnosis and intervention.Am J Clin Nutr 1991; 54:578-585.
  • [123]Sinaasappel M.Relationship between intestinal function and chloride secretion in patients with cystic fibrosis.Neth J Med 1992; 41:110-114.
  • [124]Pencharz PB,Durie PR.Pathogenesis of malnutrition in cystic fibrosis,and its treatment.Clin Nutr 2000; 19:387-394.
  • [125]Domschke S,Domschke W,Rosch W,Konturek S J,Wunsch E,Demling L.Bicarbonate and cyclic AMP content of pure human pancreatic juice in response to graded doses of synthetic secretin.Gastroenterology 1976; 70:533-536.
  • [126]Wada K,Yamadera K,Yokoyama K,Goto M,Makino I.Application of pure pancreatic juice collection to the pancreatic exocrine function test.Pancreas 1998; 16:124-128.
  • [127]Hadorn B,Johansen PG,Anderson CM.Pancreozymin secretin test of exocrine pancreatic function in cystic fibrosis and the significance of the result for the pathogenesis of the disease.Can Med Assoc J 1968; 98:377-385.
  • [128]Johansen PG,Anderson CM,Hadorn B.Cystic fibrosis of the pancreas.A generalised disturbance of water and electrolyte movement in exocrine tissues.Lancet 1968; 1:455-460.
  • [129]Kopelman H,Ferretti E,Gauthier C,Goodyer PR.Rabbit pancreatic acini express CFTR as a cAMP-activated chloride efflux pathway.Am J Physiol 1995; 269:C626-C631.
  • [130]Zeng W,Lee MG,Yan M,Diaz J,Benjamin I,Marino CR,Kopito R,Freedman S,Cotton C,Muallem S,Thomas P.Immuno and functional characterization of CFTR in submandibular and pancreatic acinar and duct cells.Am J Physiol 1997;273:C442-C455.
  • [131]Marino CR,Matovcik LM,Gorelick FS,Cohn JA.Localization of the cystic fibrosis transmembrane conductance regulator in pancreas.J Clin Invest 1991; 88:712-716.
  • [132]Whitcomb DC.Pancreatic bicarbonate secretion:role of CFTR and the sodium-bicarbonate cotransporter.Gastroenterology 1999; 117:275-277.
  • [133]Abuladze N,Lee I,Newman D,Hwang J,Boorer K,Pushkin A,Kurtz I.Molecular cloning,chromosomal localization,tissue distribution,and functional expression of the human pancreatic sodium bicarbonate cotransporter.J Biol Chem 1998; 273:17689-17695.
  • [134]Ishiguro H,Steward MC,Wilson RW,Case RM.Bicarbonate secretion in interlobular ducts from guinea-pig pancreas.J Physiol 1996; 495 (Pt 1):179-191.
  • [135]Ishiguro H,Steward MC,Lindsay AR,Case RM.Accumulation of intracellular HCO3-by Na+-HCO3-cotransport in interlobular ducts from guinea-pig pancreas.J Physiol 1996; 495 (Pt 1):169-178.
  • [136]Shumaker H,Amlal H,Frizzell R,Ulrich CD,2nd,Soleimani M.CFTR drives Na+-nHCO3-cotransport in pancreatic duct cells:a basis for defective HCO3-secretion in CF.Am J Physiol 1999;276:C16-C25.
  • [137]Novak I,Greger R.Electrophysiological study of transport systems in isolated perfused pancreatic ducts:properties of the basolateral membrane.Pflugers Arch 1988; 411:58-68.
  • [138]Novak I,Greger R.Properties of the luminal membrane of isolated perfused rat pancreatic ducts.Effect of cyclic AMP and blockers of chloride transport.Pflugers Arch 1988; 411:546-553.
  • [139]Sohma Y,Gray MA,Imai Y,Argent BE.HCO3-transport in a mathematical model of the pancreatic ductal epithelium.J Membr Biol 2000; 176:77-100.
  • [140]Lee MG,Choi JY,Luo X,Strickland E,Thomas PJ,Muallem S.Cystic fibrosis transmembrane conductance regulator regulates luminal Cl-/HCO3-exchange in mouse submandibular and pancreatic ducts.J Biol Chem 1999; 274:14670-14677.
  • [141]Namkung W,Lee JA,Ahn W,Han W,Kwon SW,Ahn DS,Kim KH,Lee MG.Ca2+ activates cystic fibrosis transmembrane conductance regulator-and Cl--dependent HCO3-transport in pancreatic duct cells.J Biol Chem 2003; 278:200-207.
  • [142]Choi JY,Muallem D,Kiselyov K,Lee MG,Thomas PJ,Muallem S.Aberrant CFTR-dependent HCO3-transport in mutations associated with cystic fibrosis.Nature 2001; 410:94-97.
  • [143]Choi JY,Lee MG,Ko S,Muallem S.Cl--dependent HCO3-transport by cystic fibrosis transmembrane conductance regulator.JOP 2001; 2:243-246.
  • [144]Ko SB,Zeng W,Dorwart MR,Luo X,Kim KH,Millen L,Goto H,Naruse S,Soyombo A,Thomas PJ,Muallem S.Gating of CFTR by the STAS domain of SLC26 transporters.Nat Cell Biol 2004; 6:343-350.
  • [145]Shcheynikov N,Wang Y,Park M,Ko SB,Dorwart M,Naruse S,Thomas PJ,Muallem S.Coupling modes and stoichiometry of Cl-/HCO3-exchange by slc26a3 and slc26a6.J Gen Physiol 2006; 127:511-524.
  • [146]Ishiguro H,Namkung W,Yamamoto A,Wang Z,Worrell RT,Xu J,Lee MG,Soleimani M.Effect of Slc26a6 deletion on apical Cl-/HCO3-exchanger activity and cAMP-stimulated bicarbonate secretion in pancreatic duct.Am J Physiol Gastrointest Liver Physiol 2007; 292:G447-G455.
  • [147]Wang Y,Soyombo AA,Shcheynikov N,Zeng W,Dorwart M,Marino CR,Thomas PJ,Muallem S.Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3-secretion:relevance to cystic fibrosis.EMBO J 2006; 25:5049-5057.
  • [148]Illek B,Tam AW,Fischer H,Machen TE.Anion selectivity of apical membrane conductance of Calu 3 human airway epithelium.Pflugers Arch 1999; 437:812-822.
  • [149]Ko SB,Shcheynikov N,Choi JY,Luo X,Ishibashi K,Thomas PJ,Kim JY,Kim KH,Lee MG,Naruse S,Muallem S.A molecular mechanism for aberrant CFTR-dependent HCO3-transport in cystic fibrosis.EMBO J 2002; 21:5662-5672.
  • [150]Shcheynikov N,Kim KH,Kim KM,Dorwart MR,Ko SB,Goto H,Naruse S,Thomas PJ,Muallem S.Dynamic control of cystic fibrosis transmembrane conductance regulator Cl-/HCO3-selectivity by external Cl-.J Biol Chem 2004; 279:21857-21865.
  • [151]Steward MC,Ishiguro H,Case RM.Mechanisms of bicarbonate secretion in the pancreatic duct.Annu Rev Physiol 2005; 67:377-409.
  • [152]Ishiguro H,Naruse S,San Roman JI,Case M,Steward MC.Pancreatic ductal bicarbonate secretion:past,present and future.JOP 2001; 2:192-197.
  • [153]Devor DC,Singh AK,Lambert LC,DeLuca A,Frizzell RA,Bridges RJ.Bicarbonate and chloride secretion in Calu-3 human airway epithelial cells.J Gen Physiol 1999; 113:743-760.
  • [154]Ishiguro H,Steward MC,Sohma Y,Kubota T,Kitagawa M,Kondo T,Case RM,Hayakawa T,Naruse S.Membrane potential and bicarbonate secretion in isolated interlobular ducts from guinea-pig pancreas.J Gen Physiol 2002; 120:617-628.
  • [155]Esterly JR,Oppenheimer EH.Cystic fibrosis of the pancreas:structural changes in peripheral airways.Thorax 1968; 23:670-675.
  • [156]Khan TZ,Wagener JS,Bost T,Martinez J,Accurso FJ,Riches DW.Early pulmonary inflammation in infants with cystic fibrosis.Am J Respir Crit Care Med 1995; 151:1075-1082.
  • [157]Noah TL,Black HR,Cheng PW,Wood RE,Leigh MW.Nasal and bronchoalveolar lavage fluid cytokines in early cystic fibrosis.J Infect Dis 1997; 175:638-647.
  • [158]Muhlebach MS,Stewart PW,Leigh MW,Noah TL.Quantitation of inflammatory responses to bacteria in young cystic fibrosis and control patients.Am J Respir Crit Care Med 1999; 160:186-191.
  • [159]Armstrong DS,Grimwood K,Carlin JB,Carzino R,Gutierrez JP,Hull J,Olinsky A,Phelan EM,Robertson CF,Phelan PD.Lower airway inflammation in infants and young children with cystic fibrosis.Am J Respir Crit Care Med 1997; 156:1197-1204.
  • [160]Armstrong DS,Hook SM,Jamsen KM,Nixon GM,Carzino R,Carlin JB,Robertson CF,Grimwood K.Lower airway inflammation in infants with cystic fibrosis detected by newborn screening.Pediatr Pulmonol 2005; 40:500-510.
  • [161]Srivastava M,Eidelman O,Zhang J,Paweletz C,Caohuy H,Yang Q,Jacobson KA,Heldman E,Huang W,Jozwik C,Pollard BS,Pollard HB.Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells.Proc Natl Acad Sci USA 2004; 101:7693-7698.
  • [162]Hajj R,Lesimple P,Nawrocki-Raby B,Birembaut P,Puchelle E,Coraux C.Human airway surface epithelial regeneration is delayed and abnormal in cystic fibrosis.J Pathol 2007; 211:340-350.
  • [163]Eidelman O,Srivastava M,Zhang J,Leighton X,Murtie J,Jozwik C,Jacobson K,Weinstein DL,Metcalf EL,Pollard HB.Control of the proinflammatory state in cystic fibrosis lung epithelial cells by genes from the TNF-alphaR/NFkappaB pathway.Mol Med 2001; 7:523-534.
  • [164]Joseph T,Look D,Ferkol T.NF-kappaB activation and sustained IL-8 gene expression in primary cultures of cystic fibrosis airway epithelial cells stimulated with Pseudomonas aeruginosa.Am J Physiol Lung Cell Mol Physiol 2005; 288:L471-L479.
  • [165]Rubin BK.CFTR is a modulator of airway inflammation.Am J Physiol Lung Cell Mol Physiol 2007; 292:L381-L382.
  • [166]Machen TE.Innate immune response in CF airway epithelia:hyperinflammatory? Am J Physiol Cell Physiol 2006; 291:C218-C230.
  • [167]Aldallal N,McNaughton EE,Manzel LJ,Richards AM,Zabner J,Ferkol TW,Look DC.Inflammatory response in airway epithelial cells isolated from patients with cystic fibrosis.Am J Respir Crit Care Med 2002; 166:1248-1256.
  • [168]Pizurki L,Morris MA,Chanson M,Solomon M,Pavirani A,Bouchardy I,Suter S.Cystic fibrosis transmembrane conductance regulator does not affect neutrophil migration across cystic fibrosis airway epithelial monolayers.Am J Pathol 2000;156:1407-1416.
  • [169]Becker MN,Sauer MS,Muhlebach MS,Hirsh AJ,Wu Q,Verghese MW,Randell SH.Cytokine secretion by cystic fibrosis airway epithelial cells.Am J Respir Crit Care Med 2004;169:645-653.
  • [170]Perez A,Issler AC,Cotton CU,Kelley TJ,Verkman AS,Davis PB.CFTR inhibition mimics the cystic fibrosis inflammatory profile.Am J Physiol Lung Cell Mol Physiol 2007; 292:L383-L395.
  • [171]Chan MM,Chmura K,Chan ED.Increased NaCl-induced interleukin-8 production by human bronchial epithelial cells is enhanced by the deltaF508/W1282X mutation of the cystic fibrosis transmembrane conductance regulator gene.Cytokine 2006; 33(6):309-316.
  • [172]Chmiel JF,Davis PB.State of the art:why do the lungs of patients with cystic fibrosis become infected and why can't they clear the infection? Respir Res 2003; 4:8.
  • [173]Regnis JA,Robinson M,Bailey DL,Cook P,Hooper P,Chan HK,Gonda I,Bautovich G,Bye PT.Mucociliary clearance in patients with cystic fibrosis and in normal subjects.Am J Respir Crit Care Med 1994; 150:66-71.
  • [174]Chace KV,Naziruddin B,Desai VC,Flux M,Sachdev GP.Physical properties of purified human respiratory mucus glycoproteins:effects of sodium chloride concentration on the aggregation properties and shape.Exp Lung Res 1989; 15:721-737.
  • [175]Chace KV,Flux M,Sachdev GP.Comparison of physicochemical properties of purified mucus glycoproteins isolated from respiratory secretions of cystic fibrosis and asthmatic patients.Biochemistry 1985; 24:7334-7341.
  • [176]Oppenheimer EH,Esterly JR.Observations in cystic fibrosis of the pancreas.Ⅱ.Neonatal intestinal obstruction.Bull Johns Hopkins Hosp 1962; 111:1-13.
  • [177]Boucher RC.Airway surface dehydration in cystic fibrosis:pathogenesis and therapy.Annu Rev Med 2007; 58:157-170.
  • [178]Boucher RC.Pathogenesis of cystic fibrosis airways disease.Trans Am Clin Climatol Assoc 2001; 112:99-107.
  • [179]Knowles M,Gatzy J,Boucher R.Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis.N Engl J Med 1981; 305:1489-1495.
  • [180]Stutts MJ,Canessa CM,Olsen JC,Hamrick M,Cohn JA,Rossier BC,Boucher RC.CFTR as a cAMP-dependent regulator of sodium channels.Science 1995; 269:847-850.
  • [181]Boucher RC.Evidence for airway surface dehydration as the initiating event in CF airway disease.J Intern Med 2007; 261:5-16.
  • [182]Mall M,Grubb BR,Harkema JR,O'Neal WK,Boucher RC.Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice.Nat Med 2004; 10:487-493.
  • [183]Grubb BR,Boucher RC.Pathophysiology of gene-targeted mouse models for cystic fibrosis.Physiol Rev 1999; 79:S 193-S214.
  • [184]de Jonge HR.Cystic fibrosis mice rehabilitated for studies of airway gland dysfunction.J Physiol 2007; 580(Pt 1):301-314.
  • [185]Quinton PM.Viscosity versus composition in airway pathology.Am J Respir Crit Care Med 1994; 149:6-7.
  • [186]Cowley EA,Govindaraju K,Lloyd DK,Eidelman DH.Airway surface fluid composition in the rat determined by capillary electrophoresis.Am J Physiol 1997; 273:L895-L899.
  • [187]Zabner J,Smith JJ,Karp PH,Widdicombe JH,Welsh MJ.Loss of CFTR chloride channels alters salt absorption by cystic fibrosis airway epithelia in vitro.Mol Cell 1998; 2:397-403.
  • [188]Joris L,Quinton PM.Filter paper equilibration as a novel technique for in vitro studies of the composition of airway surface fluid.Am J Physiol 1992; 263:L243-L248.
  • [189]Widdicombe JG.Airway Surface Liquids:Concepts and Measurements.In:Airway Mucus:Basic Mechanisms and Clinical Perspectives.Rodgers DF,Lethem MI.eds,.Basel:Birkhauser,1997,1-17.
  • [190]Hull J,Skinner W,Robertson C,Phelan P.Elemental content of airway surface liquid from infants with cystic fibrosis.Am J Respir Crit Care Med 1998; 157:10-14.
  • [191]Song Y,Thiagarajah J,Verkman AS.Sodium and chloride concentrations,pH,and depth of airway surface liquid in distal airways.J Gen Physiol 2003; 122:511-519.
  • [192]Verkman AS.Lung disease in cystic fibrosis:is airway surface liquid composition abnormal? Am J Physiol Lung Cell Mol Physiol 2001; 281:L306-L308.
  • [193]Matsui H,Grubb BR,Tarran R,Randell SH,Gatzy JT,Davis W,Boucher RC.Evidence for periciliary liquid layer depletion,not abnormal ion composition,in the pathogenesis of cystic fibrosis airway disease.Cell 1998; 95:1005-1015.
  • [194]Knowles MR,Robinson JM,Wood RE,Pue CA,Mentz WM,Wager GC,Gatzy JT,Boucher RC.Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects.J Clin Invest 1997; 100:2588-2595.
  • [195]Smith JJ,Travis SM,Greenberg EP,Welsh MJ.Cystic fibrosis airway epithelia fail to kill bacteria because of abnormal airway surface fluid.Cell 1996; 85:229-236.
  • [196]Singh PK,Jia HP,Wiles K,Hesselberth J,Liu L,Conway BA,Greenberg EP,Valore EV,Welsh MJ,Ganz T,Tack BF,McCray PB Jr.Production of beta-defensins by human airway epithelia.Proc Natl Acad Sci USA 1998; 95:14961-14966.
  • [197]Singh PK,Tack BF,McCray PB Jr.,Welsh MJ.Synergistic and additive killing by antimicrobial factors found in human airway surface liquid.Am J Physiol Lung Cell Mol Physiol 2000; 279:L799-L805.
  • [198]Travis SM,Conway BA,Zabner J,Smith JJ,Anderson NN,Singh PK,Greenberg EP,Welsh MJ.Activity of abundant antimicrobials of the human airway.Am J Respir Cell Mol Biol 1999; 20:872-879.
  • [199]Quinton PM.Water Metabolism:Protozoa to man.In:Comparative Animal Nutrition.3rd ed.Recighl M.ed.Basel:S.Karger,1979,100-231.
  • [200]Quinton PM.The neglected ion:HCO3-.Nat Med 2001; 7:292-293.
  • [201]Livingston EH,Miller J,Engel E.Bicarbonate diffusion through mucus.Am J Physiol 1995; 269:G453-G457.
  • [202]Allen A,Flemstrom G,Garner A,Kivilaakso E.Gastroduodenal mucosal protection.Physiol Rev 1993; 73:823-857.
  • [203]Trout L,King M,Feng W,Inglis SK,Ballard ST.Inhibition of airway liquid secretion and its effect on the physical properties of airway mucus.Am J Physiol 1998; 274:L258-L263.
  • [204]Joo NS,Krouse ME,Wu JV,Saenz Y,Jayaraman S,Verkman AS,Wine JJ.HCO3-transport in relation to mucus secretion from submucosal glands.JOP 2001; 2:280-284.
  • [205]App EM,Danzl G,King M.In vitro sputum rheology changes in cystic fibrosis,chronic bronchitis and asthma lung diseases following the application of different salt solutions.Am J Crit Care Med 1996; 153:A824.
  • [206]Cheng HF,Lin HC,Yu CT,Kuo HP.Effect of aerosolized alkaline solution on patients with bronchiectasis with sputum hypersecretion.Eur Respir J 1996; 8:390s.
  • [207]Rhee CS,Majima Y,Cho JS,Arima S,Min YG,Sakakura Y.Effects of mucokinetic drugs on rheological properties of reconstituted human nasal mucus.Arch Otolaryngol Head Neck Surg 1999; 125:101-105.
  • [208]Haidl P,Schonhofer B,Siemon K,Kohler D.Inhaled isotonic alkaline versus saline solution and radioaerosol clearance in chronic cough.Eur Respir J 2000; 16:1102-1108.
  • [209]Holma B.Influence of buffer capacity and pH-dependent rheological properties of respiratory mucus on health effects due to acidic pollution.Sci Total Environ 1985; 41:101-123.
  • [210]Holma B,Hegg PO.pH-and protein-dependent buffer capacity and viscosity of respiratory mucus.Their interrelationships and influence on health.Sci Total Environ 1989; 84:71-82.
  • [211]Bhaskar KR,Gong DH,Bansil R,Pajevic S,Hamilton JA,Turner BS,LaMont JT.Profound increase in viscosity and aggregation of pig gastric mucin at low pH.Am J Physiol 1991;261:G827-G832.
  • [212]Cao X,Bansil R,Bhaskar KR,Turner BS,LaMont JT,Niu N,Afdhal NH.pH-dependent conformational change of gastric mucin leads to sol-gel transition.Biophys J 1999; 76:1250-1258.
  • [213]Luk CK,Dulfano MJ.Effect of pH,viscosity and ionic-strength changes on ciliary beating frequency of human bronchial explants.Clin Sci (Lond) 1983; 64:449-451.
  • [214]Coakley RD,Grubb BR,Paradiso AM,Gatzy JT,Johnson LG,Kreda SM,O'Neal WK,Boucher RC.Abnormal surface liquid pH regulation by cultured cystic fibrosis bronchial epithelium.Proc Natl Acad Sci USA 2003; 100:16083-16088.
  • [215]Sanderson MJ,Dirksen ER.Mechanosensitive and beta-adrenergic control of the ciliary beat frequency of mammalian respiratory tract cells in culture.Am Rev Respir Dis 1989; 139:432-440.
  • [216]Duneclift S,Wells U,Widdicombe J.Estimation of thickness of airway surface liquid in ferret trachea in vitro.J Appl Physiol 1997; 83:761-767.
  • [217]Widdicombe JH,Bastacky SJ,Wu DX,Lee CY.Regulation of depth and composition of airway surface liquid.Eur Respir J 1997; 10:2892-2897.
  • [218]Smith JJ,Welsh MJ.cAMP stimulates bicarbonate secretion across normal,but not cystic fibrosis airway epithelia.J Clin Invest 1992; 89:1148-1153.
  • [219]Trout L,Townsley MI,Bowden AL,Ballard ST.Disruptive effects of anion secretion inhibitors on airway mucus morphology in isolated perfused pig lung.J Physiol 2003; 549:845-853.
  • [220]Garcia AB,Quinton P.HCO3-enhances mucus release in mouse small intestine.Pediatr Pulmonol 2006; 21(Suppl):243.
  • [221]Cystic Fibrosis Mutation Database.Cystic Fibrosis GeneticAnalysis Consortium.2003.
  • [222]Quinton PM.ed.Fluid and Electrolyte Abnormalities in Exocrine Glands in Cystic Fibrosis.San Francisco:San Francisco Press,Inc.,1982,298.
  • [223]Quinton PM.Cystic fibrosis:a disease in electrolyte transport.Faseb J 1990; 4:2709-2717.
  • [224]Snyder JD,Merson MH.The magnitude of the global problem of acute diarrhoeal disease:a review of active surveillance data.Bull World Health Organ 1982; 60:605-613.
  • [225]Thapar N,Sanderson IR.Diarrhoea in children:an interface between developing and developed countries.Lancet 2004; 363:641-653.
  • [226]Quinton PM.Human genetics.What is good about cystic fibrosis? Curr Biol 1994; 4:742-743.
  • [227]Gabriel SE,Brigman KN,Koller BH,Boucher RC,Stutts MJ.Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model.Science 1994; 266:107-109.
  • [228]Cuthbert AW,Hickman ME,MacVinish LJ,Evans MJ,Colledge WH,Ratcliff R,Seale PW,Humphrey PP.Chloride secretion in response to guanylin in colonic epithelial from normal and transgenic cystic fibrosis mice.Br J Pharmacol 1994; 112:31-36.
  • [229]Best JA,Quinton PM.Simple salivary secretion assay for drug efficacy for cystic fibrosis.Exp Physiol 2005; 90(2):189-193.
  • [230]Cuthbert AW,Halstead J,Ratcliff R,Colledge WH,Evans MJ.The genetic advantage hypothesis in cystic fibrosis heterozygotes:a murine study.J Physiol 1995; 482 (Pt 2):449-454.
  • [231]Hogenauer C,Santa Aha CA,Porter JL,Millard M,Gelfand A,Rosenblatt RL,Prestidge CB,Fordtran JS.Active intestinal chloride secretion in human carriers of cystic fibrosis mutations:an evaluation of the hypothesis that heterozygotes have subnormal active intestinal chloride secretion.Am J Hum Genet 2000; 67:1422-1427.
  • [232]Estivill X,Bancells C,Ramos C.Geographic distribution and regional origin of 272 cystic fibrosis mutations in European populations.The Biomed CF Mutation Analysis Consortium.Hum Mutat 1997; 10:135-154.
  • [233]Dumur V,Gervais R,Rigot JM,Delomel-Vinner E,Decaestecker B,Lafitte JJ,Roussel P.Congenital bilateral absence of the vas deferens (CB AVD) and cystic fibrosis transmembrane regulator (CFTR):correlation between genotype and phenotype.Hum Genet 1996; 97:7-10.
  • [234]Brown D,Breton S.H+V-ATPase-dependent luminal acidification in the kidney collecting duct and the epididymis/vas deferens:vesicle recycling and transcytotic pathways.J Exp Biol 2000; 203 (Pt 1):137-145.
  • [235]Oppenheimer EA,Case AL,Esterly JR,Rothberg RM.Cervical mucus in cystic fibrosis:a possible cause of infertility.Am J Obstet Gynecol 1970; 108:673-674.
  • [236]Wang XF,Zhou CX,Shi QX,Yuan YY,Yu MK,Ajonuma LC,Ho LS,Lo PS,Tsang LL,Liu Y,Lam SY,Chan LN,Zhao WC,Chung YW,Chan HC.Involvement of CFTR in uterine bicarbonate secretion and the fertilizing capacity of sperm.Nat Cell Biol 2003; 5:902-906.
  • [237]Davis PB.Pathophysiology of cystic fibrosis with emphasis on salivary gland involvement.J Dent Res 1987; 66:667-671.
  • [238]Cohn JA,Strong TV,Picciotto MR,Nairn AC,Collins FS,Fitz JG.Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells.Gastroenterology 1993; 105:1857-1864.
  • [239]Curtis CM,Martin LC,Higgins CF,Colledge WH,Hickman ME,Evans MJ,MacVinish LJ,Cuthbert AW.Restoration by intratracheal gene transfer of bicarbonate secretion in cystic fibrosis mouse gallbladder.Am J Physiol 1998; 274:G1053-G1060.
  • [240]Wine JJ.Cystic fibrosis:the "bicarbonate before chloride"hypothesis.Curt Biol 2001; 11:R463-R466.
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