Skip to main content
PMC home page
Thorax logoLink to Thorax
. 1991 Feb;46(2):124–130. doi: 10.1136/thx.46.2.124

Cystic fibrosis. 4. Abnormalities of airway epithelial function and the implications of the discovery of the cystic fibrosis gene.

A W Cuthbert 1
PMCID: PMC462974  PMID: 1707559

Abstract

Details of ion transporting abnormalities in cystic fibrosis airway epithelium are now known. The central hypothesis, that excessive drying of the airway surfaces is a primary event that leads to all the manifestations of the respiratory insufficiency in cystic fibrosis, is not proved. The hypothesis is, however, consistent with the known transporting abnormalities and is strengthened by the modest clinical improvement produced by a strategy designed to correct the transporting abnormalities. The discovery of the cystic fibrosis gene, together with the presumed structure of the protein product, provides a focal point that must eventually connect the functional abnormalities with the genetic defect. The cellular function of the cystic fibrosis transmembrane regulator must now be the major target in research on cystic fibrosis. Strategies for treatment based on known cellular and molecular abnormalities are beginning to emerge but will be undoubtedly more focused once the responsibility of the cystic fibrosis transmembrane regulator is known.

Full text

PDF

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aceves J., Cuthbert A. W. Uptake of [3H]benzamil at different sodium concentrations. Inferences regarding the regulation of sodium permeability. J Physiol. 1979 Oct;295:491–504. doi: 10.1113/jphysiol.1979.sp012982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boucher R. C., Cheng E. H., Paradiso A. M., Stutts M. J., Knowles M. R., Earp H. S. Chloride secretory response of cystic fibrosis human airway epithelia. Preservation of calcium but not protein kinase C- and A-dependent mechanisms. J Clin Invest. 1989 Nov;84(5):1424–1431. doi: 10.1172/JCI114316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boucher R. C., Stutts M. J., Knowles M. R., Cantley L., Gatzy J. T. Na+ transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation. J Clin Invest. 1986 Nov;78(5):1245–1252. doi: 10.1172/JCI112708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bradley G., Juranka P. F., Ling V. Mechanism of multidrug resistance. Biochim Biophys Acta. 1988 Aug 3;948(1):87–128. doi: 10.1016/0304-419x(88)90006-6. [DOI] [PubMed] [Google Scholar]
  5. Brayden D. J., Hanley M. R., Thastrup O., Cuthbert A. W. Thapsigargin, a new calcium-dependent epithelial anion secretagogue. Br J Pharmacol. 1989 Nov;98(3):809–816. doi: 10.1111/j.1476-5381.1989.tb14609.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cheng P. W., Boat T. F., Cranfill K., Yankaskas J. R., Boucher R. C. Increased sulfation of glycoconjugates by cultured nasal epithelial cells from patients with cystic fibrosis. J Clin Invest. 1989 Jul;84(1):68–72. doi: 10.1172/JCI114171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cheng S. H., Gregory R. J., Marshall J., Paul S., Souza D. W., White G. A., O'Riordan C. R., Smith A. E. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell. 1990 Nov 16;63(4):827–834. doi: 10.1016/0092-8674(90)90148-8. [DOI] [PubMed] [Google Scholar]
  8. Cotton C. U., Stutts M. J., Knowles M. R., Gatzy J. T., Boucher R. C. Abnormal apical cell membrane in cystic fibrosis respiratory epithelium. An in vitro electrophysiologic analysis. J Clin Invest. 1987 Jan;79(1):80–85. doi: 10.1172/JCI112812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cuthbert A. W., Brayden D. J., Dunne A., Smyth R. L., Wallwork J. Altered sensitivity to amiloride in cystic fibrosis. Observations using cultured sweat glands. Br J Clin Pharmacol. 1990 Feb;29(2):227–234. doi: 10.1111/j.1365-2125.1990.tb03624.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cuthbert A. W., Fanelli G. M. Effects of some pyrazinecarboxamides on sodium transport in frog skin. Br J Pharmacol. 1978 May;63(1):139–149. doi: 10.1111/j.1476-5381.1978.tb07783.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cuthbert A. W., Margolius H. S. Kinins stimulate net chloride secretion by the rat colon. Br J Pharmacol. 1982 Apr;75(4):587–598. doi: 10.1111/j.1476-5381.1982.tb09178.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Foxwell B. M., Mackie A., Ling V., Ryffel B. Identification of the multidrug resistance-related P-glycoprotein as a cyclosporine binding protein. Mol Pharmacol. 1989 Oct;36(4):543–546. [PubMed] [Google Scholar]
  13. Frizzell R. A., Rechkemmer G., Shoemaker R. L. Altered regulation of airway epithelial cell chloride channels in cystic fibrosis. Science. 1986 Aug 1;233(4763):558–560. doi: 10.1126/science.2425436. [DOI] [PubMed] [Google Scholar]
  14. Gregory R. J., Cheng S. H., Rich D. P., Marshall J., Paul S., Hehir K., Ostedgaard L., Klinger K. W., Welsh M. J., Smith A. E. Expression and characterization of the cystic fibrosis transmembrane conductance regulator. Nature. 1990 Sep 27;347(6291):382–386. doi: 10.1038/347382a0. [DOI] [PubMed] [Google Scholar]
  15. Hwang T. C., Lu L., Zeitlin P. L., Gruenert D. C., Huganir R., Guggino W. B. Cl- channels in CF: lack of activation by protein kinase C and cAMP-dependent protein kinase. Science. 1989 Jun 16;244(4910):1351–1353. doi: 10.1126/science.2472005. [DOI] [PubMed] [Google Scholar]
  16. Jetten A. M., Yankaskas J. R., Stutts M. J., Willumsen N. J., Boucher R. C. Persistence of abnormal chloride conductance regulation in transformed cystic fibrosis epithelia. Science. 1989 Jun 23;244(4911):1472–1475. doi: 10.1126/science.2472008. [DOI] [PubMed] [Google Scholar]
  17. Kerem B., Rommens J. M., Buchanan J. A., Markiewicz D., Cox T. K., Chakravarti A., Buchwald M., Tsui L. C. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989 Sep 8;245(4922):1073–1080. doi: 10.1126/science.2570460. [DOI] [PubMed] [Google Scholar]
  18. Kilburn K. H. A hypothesis for pulmonary clearance and its implications. Am Rev Respir Dis. 1968 Sep;98(3):449–463. doi: 10.1164/arrd.1968.98.3.449. [DOI] [PubMed] [Google Scholar]
  19. Knowles M. R., Stutts M. J., Spock A., Fischer N., Gatzy J. T., Boucher R. C. Abnormal ion permeation through cystic fibrosis respiratory epithelium. Science. 1983 Sep 9;221(4615):1067–1070. doi: 10.1126/science.6308769. [DOI] [PubMed] [Google Scholar]
  20. Knowles M. R., Stutts M. J., Yankaskas J. R., Gatzy J. T., Boucher R. C., Jr Abnormal respiratory epithelial ion transport in cystic fibrosis. Clin Chest Med. 1986 Jun;7(2):285–297. [PubMed] [Google Scholar]
  21. Knowles M., Gatzy J., Boucher R. Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis. N Engl J Med. 1981 Dec 17;305(25):1489–1495. doi: 10.1056/NEJM198112173052502. [DOI] [PubMed] [Google Scholar]
  22. Knowles M., Gatzy J., Boucher R. Relative ion permeability of normal and cystic fibrosis nasal epithelium. J Clin Invest. 1983 May;71(5):1410–1417. doi: 10.1172/JCI110894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kunzelmann K., Pavenstädt H., Greger R. Properties and regulation of chloride channels in cystic fibrosis and normal airway cells. Pflugers Arch. 1989 Nov;415(2):172–182. doi: 10.1007/BF00370589. [DOI] [PubMed] [Google Scholar]
  24. Leikauf G. D., Ueki I. F., Nadel J. A., Widdicombe J. H. Bradykinin stimulates Cl secretion and prostaglandin E2 release by canine tracheal epithelium. Am J Physiol. 1985 Jan;248(1 Pt 2):F48–F55. doi: 10.1152/ajprenal.1985.248.1.F48. [DOI] [PubMed] [Google Scholar]
  25. Li M., McCann J. D., Liedtke C. M., Nairn A. C., Greengard P., Welsh M. J. Cyclic AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium. Nature. 1988 Jan 28;331(6154):358–360. doi: 10.1038/331358a0. [DOI] [PubMed] [Google Scholar]
  26. Olver R. E., Ramsden C. A., Strang L. B., Walters D. V. The role of amiloride-blockable sodium transport in adrenaline-induced lung liquid reabsorption in the fetal lamb. J Physiol. 1986 Jul;376:321–340. doi: 10.1113/jphysiol.1986.sp016156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Rich D. P., Anderson M. P., Gregory R. J., Cheng S. H., Paul S., Jefferson D. M., McCann J. D., Klinger K. W., Smith A. E., Welsh M. J. Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature. 1990 Sep 27;347(6291):358–363. doi: 10.1038/347358a0. [DOI] [PubMed] [Google Scholar]
  28. Riordan J. R., Rommens J. M., Kerem B., Alon N., Rozmahel R., Grzelczak Z., Zielenski J., Lok S., Plavsic N., Chou J. L. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989 Sep 8;245(4922):1066–1073. doi: 10.1126/science.2475911. [DOI] [PubMed] [Google Scholar]
  29. Rommens J. M., Iannuzzi M. C., Kerem B., Drumm M. L., Melmer G., Dean M., Rozmahel R., Cole J. L., Kennedy D., Hidaka N. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989 Sep 8;245(4922):1059–1065. doi: 10.1126/science.2772657. [DOI] [PubMed] [Google Scholar]
  30. Schoumacher R. A., Shoemaker R. L., Halm D. R., Tallant E. A., Wallace R. W., Frizzell R. A. Phosphorylation fails to activate chloride channels from cystic fibrosis airway cells. Nature. 1987 Dec 24;330(6150):752–754. doi: 10.1038/330752a0. [DOI] [PubMed] [Google Scholar]
  31. Stutts M. J., Cotton C. U., Yankaskas J. R., Cheng E., Knowles M. R., Gatzy J. T., Boucher R. C. Chloride uptake into cultured airway epithelial cells from cystic fibrosis patients and normal individuals. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6677–6681. doi: 10.1073/pnas.82.19.6677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Valdivia H. H., Dubinsky W. P., Coronado R. Reconstitution and phosphorylation of chloride channels from airway epithelium membranes. Science. 1988 Dec 9;242(4884):1441–1444. doi: 10.1126/science.2462280. [DOI] [PubMed] [Google Scholar]
  33. Welsh M. J., Liedtke C. M. Chloride and potassium channels in cystic fibrosis airway epithelia. 1986 Jul 31-Aug 6Nature. 322(6078):467–470. doi: 10.1038/322467a0. [DOI] [PubMed] [Google Scholar]
  34. Widdicombe J. H. Cystic fibrosis and beta-adrenergic response of airway epithelial cell cultures. Am J Physiol. 1986 Oct;251(4 Pt 2):R818–R822. doi: 10.1152/ajpregu.1986.251.4.R818. [DOI] [PubMed] [Google Scholar]
  35. Widdicombe J. H., Welsh M. J., Finkbeiner W. E. Cystic fibrosis decreases the apical membrane chloride permeability of monolayers cultured from cells of tracheal epithelium. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6167–6171. doi: 10.1073/pnas.82.18.6167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Yankaskas J. R., Cotton C. U., Knowles M. R., Gatzy J. T., Boucher R. C. Culture of human nasal epithelial cells on collagen matrix supports. A comparison of bioelectric properties of normal and cystic fibrosis epithelia. Am Rev Respir Dis. 1985 Dec;132(6):1281–1287. doi: 10.1164/arrd.1985.132.6.1281. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES