Lack of applicability of the Enterocyte Chloride ion secretion paradigm to the Pathology of Cystic Fibrosis
DOI:
https://doi.org/10.29328/journal.aaai.1001007Abstract
This review examines of the concept of a defective chloride channel in epithelial cells being a major cause of cystic fibrotic pathophysiology. The central concept of the defective chloride ion channel paradigm is that faulty CFTR protein or failed delivery of CFTR protein to the mucosal membrane of epithelial cells is the basis of cystic fibrosis. Defective placement or function of CFTR prevents hydration of bronchial mucus that is normally caused by epithelial cells; these are capable through chloride ion secretion of transporting fluid to the mucosal surface. This concept relies heavily on a paradigm taken from intestinal physiology-namely that the intestinal epithelial cell secretes chloride ion and fluid and that this has conferred heterozygote selective advantage in carriers of the cystic fibrosis gene. This present review examines the evidence for that hypothesis and assembles evidence from past studies that it is the smooth muscle cell that is of greater relevance. This review does not aim to provide an overview of current research into cystic fibrosis. The intention is to provide an overview of past research that led to the concept of a failure of epithelial cells to hydrate bronchial mucus because of compromised CFTR function. It is important to present all past evidence for aspects of the chloride secretion hypothesis and its associated heterozygote advantage concept so that the important evidential milestones can be re-assessed.References
Lucas ML. Diarrhoeal disease through enterocyte secretion: a doctrine untroubled by proof. Exp Physiol. 2010; 95: 479-484. Ref.: https://goo.gl/3fu4M7
Alton EWFW, Armstrong DK, Ashby D, Bayfield KJ, Bilton D, et al. A randomised, double blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis. Efficiency and Mechanism Evaluation. 2016. Ref.: https://goo.gl/o5M6Ud
Lucas ML. Amendments to the theory underlying Ussing chamber data of chloride ion secretion after bacterial enterotoxin exposure. J Theor Biol. 2005; 234: 21-37. Ref.: https://goo.gl/ZJd863
Lucas ML. A reconsideration of the evidence for Escherichia coli STa (heat stable) enterotoxin driven fluid secretion: a new view of STa action and a new paradigm for fluid absorption. J Appl Microbiol. 2001; 90: 7-26. Ref.: https://goo.gl/vhVnKT
Lucas ML, Gilligan LC, Whitelaw CC, Wynne PJ, Morrison JD. Lack of restoration in vivo by K+-channel modulators of jejunal fluid absorption after heat stable Escherichia coli enterotoxin (STa) challenge J Trop Med. 2011; Article ID 853686: 7. Ref: https://goo.gl/92bfe1
Strombeck DR. The production of intestinal fluid by cholera toxin in the rat. Proc Soc exp Biol Med. 1972; 140: 297-303. Ref: https://goo.gl/vSkb5k
Lucas ML, Morrison JD. An investigation into the relationship between small intestinal fluid secretion and systemic arterial blood pressure in the anaesthetized rat. Physiological Reports. 2015;3, e12407, 1-14. Ref: https://goo.gl/VgESw6
Tsuji LC, Buchwald M, Barker D, Braman JC, Knowlton R, et al. Cystic fibrosis locus defined by a genetically linked polymorphic DNA marker. Science. 1985; 230:1054-1057. Ref.: https://goo.gl/pkvGxi
Rommens JM, Iannuzzi MC, Keren BS, Drumm ML, Melmer G, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989; 245: 1059-1064. Ref.: https://goo.gl/bS1fNg
Danks DM, Allan J, Anderson CM. A genetic study of fibrocystic disease of the pancreas. Ann Human Genet (Lond). 1965; 28: 323-356. Ref.: https://goo.gl/f76C63
Knudson AG Jr, Wayne L, Hallett WY. On the selective advantage of cystic fibrosis heterozygote. Amer J Hum Genet. 1967; 19: 388-392. Ref.: https://goo.gl/TH4ij7
Quinton PM. Abnormalities in electrolyte secretion in cystic fibrosis Eds: Quinton PM, Martinez RM, Hopfer U. San Francisco Press, San Francisco, USA. 1982; 53-76.
Barua D. A history of cholera. Cholera. 1992; 1-36. Ref.: https://goo.gl/kKp2dC
De SN. Cholera. Oliver & Boyd. Edinburgh & London. UK. 1961.
Renfrew C. Archaeology and language; the puzzle of Indo-European origins. University of Chicago Press, Chicago, USA. 1987.
Mallory JP. In search of the indo-europeans: language, archaeology and myth; Thames & Hudson. 1989.
Quinton PM. Physiological basis of cystic fibrosis: a historical perspective. Physiol Rev. 1999; 79: 3-22. Ref.: https://goo.gl/pTRbza
Lucas ML, Thom MM, Bradley JM, O’Reilly NF, McIlvenny TJ, et al. Escherichia coli heat stable (STa) enterotoxin and the upper small intestine: lack of evidence in vivo for net fluid secretion. J mem Biol. 2005; 206: 29-42. Ref.: https://goo.gl/EQjUHY
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. Ref.: https://goo.gl/V6W6UR
Araki H, Field M, Shwachman H. A new assay for cystic fibrosis factor: effects of sera from patients with cystic fibrosis on the in vivo electrical properties of rat jejunum. Pediatr Res. 1975; 9: 932-934. Ref.: https://goo.gl/bmFZHi
Gilmore JP, Davis M, Gibbs GE. Influence of cystic fibrotic and heterozygous serum on rat jejunum. Proc Soc Exp Biol Med. 1978; 157: 70-74. Ref.: https://goo.gl/jNnHeG
Tucker RD, Gibbs GE, Christensen MB. Cystic fibrosis serum effect on short circuit current of rat jejunum. Pediatr Res. 1979; 13: 1371-1374. Ref.: https://goo.gl/Un1rzd
Will PC, Boat TF, Hopfer U. Evidence against a specific effect of serum from patients with a cystic fibrosis on sodium-dependent glucose transport in the rat jejunum. Pediatr Res. 1979; 13: 1129-1133. Ref.: https://goo.gl/ZLfyRM
Berschneider HM, Knowles MR, Azizkhan RG, Boucher RC, Tobey NA, et al. Altered intestinal chloride transport in cystic fibrosis. FASEB J. 1988; 2: 2625-2629. Ref.: https://goo.gl/aB6qKJ
Taylor CJ, Baxter P, Hardcastle J, Hardcastle PT. Absence of secretory response in jejunal biopsy samples from children with cystic fibrosis. Lancet. 1987; 107-108. Ref.: https://goo.gl/ZDnDDC
Taylor CJ, Baxter P, Hardcastle J, Hardcastle PT. Failure to induce secretion in jejunal biopsies from children with cystic fibrosis. Gut. 1988; 29: 107-108. Ref.: https://goo.gl/AD3pLW
Baxter P, Wilson AJ, Read NW, Hardcastle J, Hardcastle PT, et al. Abnormal jejunal potential difference in cystic fibrosis. Lancet. 1989; 464-466. Ref.: https://goo.gl/L5xG34
O’Loughlin EV, Hunt DM, Gaskin KJ, Stiel D, Bruzuszcak IM, et al. Abnormal epithelial transport in cystic fibrosis jejunum. Am J Physiol. 1991; 260: 758-763. Ref.: https://goo.gl/LZcFW1
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: 449-454. Ref.: https://goo.gl/7DsAnS
Lucas ML. An alternative explanation for the occurrence of short circuit current increases in the small intestine following challenge by bacterial enterotoxins. Med Hypotheses. 2013; 81: 601-606. Ref.: https://goo.gl/1yyi6p
Cuthbert AW, Hickman ME, MacVinish LJ, Evans MJ, Colledge WH, et al. Chloride secretion in response to guanylin in colonic epithelia from normal and transgenic cystic fibrosis mice. Br J Pharmacol. 1994; 112: 31-36. Ref.: https://goo.gl/US1nns
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. Ref.: https://goo.gl/5KaAp4
Grubb BR, Gabriel SE. Intestinal physiology and pathology in gene-targeted mouse models of cystic fibrosis. Am J Physiol. 1997; 273: 258-266. Ref.: https://goo.gl/VLg6jk
Zhou L, Dey CR, Wert SE, Duvall MD, Frizzell RA, et al. Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR. Science. 1994; 266: 1705-1709. Ref.: https://goo.gl/sp9v1F
Teune TM, Timmers-Reker AJM, Bouquet J, Bijman J, De Jonge HR, et al. In vivo measurement of chloride and water secretion in the jejunum of cystic fibrosis patients. Pediatr Res. 1996; 40: 522-527. Ref.: https://goo.gl/o7PhYQ
Russo MA, Högenauer C, Coates SW Jr, Santa Ana CA, Porter JL, et al. Abnormal passive chloride absorption in cystic fibrosis jejunum functionally opposes the classic chloride secretory defect. J Clin Invest. 2003; 112: 118-124. Ref.: https://goo.gl/rZyhDt
Högenauer C, Santa Ana CA, Porter JL, Millard M, Gelfand A, et al. 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; 6: 1422-1427. Ref.: https://goo.gl/Z7GCf3
Goldstein JL, Sahi J, Bhuva M, Layden TJ, Rao MC. Escherichia coli heat-stable enterotoxin-mediated colonic Cl- secretion is absent in cystic fibrosis. Gastroenterology. 1994; 107: 950-956. Ref.: https://goo.gl/Zb9wah
Grubb BR. Ion transport across the jejunum in normal and cystic fibrotic mice. Am J Physiol. 1995; 268: 505-513. Ref.: https://goo.gl/Bg5fZx
Antonowicz I, Lebenthal E, Schwachman H. Dissacharidase activities in small intestinal mucosa in patients with cystic fibrosis. J Pediatr. 1978; 92: 214-219. Ref.: https://goo.gl/pUKXxp
Baxter P, Goldhill J, Hardcastle J, Hardcastle PT, Taylor CJ. Enhanced intestinal glucose and alanine transport in cystic fibrosis. Gut. 1990; 31: 817-820. https://goo.gl/LWQC87
Frase LL, Strickland AD, Kachel GW, Krejs GJ. Enhanced glucose absorption in the jejunum of patients with cystic fibrosis. Gastroenterology. 1985; 88: 478-484. Ref.: https://goo.gl/7T33Kx
Bradford EM, Sartor MA, Gawenis LR, Clarke LL, Shull GE. Reduced NHE3-mediated Na+ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice. Am J Physiol. 2009; 29: 886-898. Ref.: https://goo.gl/FwSK2P
Drlica K. Understanding DNA and gene cloning: A guide for the curious. Wiley & Sons, New York, USA. 1997.
Schroeder SA, Gaughan DM, Swift M. Protection against bronchial asthma by CFTR delta F508 mutation: A heterozygote advantage in cystic fibrosis. Nat Med. 1995; 1: 703-705. Ref.: https://goo.gl/d7bvbr
Peach SL, Boriello SP, Gaya H, Barclay FE, Welch AR. Asymptomatic carriage of Clostridium difficile in patients with cystic fibrosis. J Clin Pathol. 1986; 39: 1013-1018. Ref.: https://goo.gl/KodCR8
Monaghan TM, Robins A, Knox A, Sewell HF, Mahida YR. Circulating antibody and memory B-cell responses to C. difficile toxins A and B in patients with C. difficile-associated diarrhoea, inflammatory bowel disease and cystic fibrosis. Plos One. 2013; 8: 74452. Ref.: https://goo.gl/LjpNww
Cohen JC, Lundblad LKA, Bates JHT, Levitsky M, Larson JE. The “Goldilocks Effect” in cystic fibrosis: identification of a lung phenotype in the cftr knockout and heterozygous mouse. BMC Genet. 2004; 5: 21. Ref.: https://goo.gl/f6KR6o
Hildebrandt J. Comparison of mathematical models for cat lung and viscoelastic balloon derived by Laplace transform methods from pressure-volume data. Bull Math Biophys. 1969; 31: 651-667. Ref.: https://goo.gl/YvnnoM
Hantos Z, Daroczy B, Suki B, Nagy S, Fredberg JJ. Input impedance and peripheral inhomogeneity of dog lungs. J Appl Physiol. 1992; 72: 168-178. Ref.: https://goo.gl/7wCMCe
Risse PA, Kachmar L, Matusovsky OS, Novali M, Gil FR, et al. Ileal smooth muscle dysfunction and remodeling in cystic fibrosis. Am J Physiol Gastrointest Liver Physiol. 2012; 303: 1-8. Ref.: https://goo.gl/AUkByv
Robert R, Norez C, Becq F. Disruption of CFTR chloride channel alters mechanical properties and cAMP-dependent Cl- transport of mouse aortic smooth muscle cells. J Physiol. 2005; 568: 483-495. Ref.: https://goo.gl/NdSMYm
Peter BF, Lidington D, Harada A, Bolz HJ, Vogel L, et al. Role of sphingosine-1-phosphate phosphohydrolase 1 in the regulation of resistance artery tone. Circ Res. 2008; 103: 315-324. Ref.: https://goo.gl/N9XALj
Eichler HG, Eichler I, Lewiston N, Blaschke TF, Hoffman BB. Responsiveness of superficial hand veins to adrenergic stimuli in patients with cystic fibrosis. Clin Sci (Lond). 1989; 76: 283-287. Ref.: https://goo.gl/Pm9BBU
Alcolado NG, Conrad DJ, Poroca D, Alshafie W, Chappe FG, et al. Cystic fibrosis transmembrane conductance regulator dysfunction in VIP knockout mice. Am J Physiol Cell Physiol. 2014; 307: 195-207. Ref.: https://goo.gl/dk4XZB
Efrati O, Barak A, Modan-Moses D, Augarten A, Vilozni D, et al. Liver cirrhosis and portal hypertension in cystic fibrosis. Eur J Gastroenterol Hepatol. 2003; 15: 1073-1078. Ref.: https://goo.gl/T16n1X
Lack EE. Carotid body hypertrophy in patients with cystic fibrosis and congenital cyanotic heart disease. Hum Pathol. 1977; 8: 39-50. Ref.: https://goo.gl/pZpuaz
Dinh Xuan AT, Higenbottam TW, Pepke-Zaba J, Clelland C, Wallwork J. Reduced endothelium-dependent relaxation of cystic fibrosis pulmonary arteries. Eur J Pharmacol. 1989; 163: 401-403. Ref.: https://goo.gl/Bc5E2Z
Pan J, Luk C, Kent G, Lutz E, Yeger H. Pulmonary neuroendocrine cells airway innervation and smooth muscle are altered in cftr null mice. Am J Respir Cell Mol Biol. 2006; 35: 320-326. Ref.: https://goo.gl/c7Na3w
De Lisle RC, Sewell R, Meldi L. Enteric circular muscle dysfunction in the cystic fibrosis mouse small intestine. Neurogastroenterol Motil. 2010; 22: 341-387. Ref.: https://goo.gl/C68g2E
Matchkov VV, Dam VS, Bødtkjer DMB, Aalkjær C. Transport and function of chloride in vascular smooth muscles. J Vasc Res. 2013; 50: 69-87. Ref.: https://goo.gl/qi4vKN
Weyer A, Huott P, Liu W, McRoberts JA, Dharmsathaphorn K. Chloride secretory mechanism induced by prostaglandin-E1 in a colonic epithelial cell line. J Clin Invest. 1985; 76: 1828-1836. Ref.: https://goo.gl/Gq4VK5
Coates SW, Hoegenauer C, Santa Ana CA, Rosenblatt RL, Emmett M, et al. Inhibition of neutral sodium ion absorption in patients with cystic fibrosis. Gastroenterol. 2004; 127: 65-72.
Hubert D, Bui S, Marguet C, Colomb-Jung V, Murris-Espin M, et al. Nouvelles therapeutiique de la mucoviscidose ciblant le gene ou la protein CFTR. Revue des Maladies Respiratoires. 2016. Ref.: https://goo.gl/DKpJGn
Ramsey BW, Davies J, McElvaney NG. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011; 365: 1663-1672. Ref.: https://goo.gl/NvCXRJ
Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013; 187: 1219-1225. Ref.: https://goo.gl/AVkpYk
Flume PA, Liou TG, Borowitz DS, et al. Ivacaftor in subjects with cystic fibrosis who are homogenous for the F508del-CFTR mutation. Chest. 2012; 142: 718-724.
Adam RJ, Hisert KB, Dodd JD, Grogan B, Launspach JL, et al. Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities. JCI Insight. 2016; 1: 86183. Ref.: https://goo.gl/5AzTiq
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