Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Submucosal glands are the predominant site of CFTR expression in the human bronchus

Abstract

We have used in situ hybridization and immunocytochemistry to characterize the cellular distribution of cystic fibrosis (CF) gene expression in human bronchus. The cystic fibrosis transmembrane conductance regulator (CFTR) was primarily localized to cells of submucosal glands in bronchial tissues from non–CF individuals notably in the serous component of the secretory tubules as well as a subpopulation of cells in ducts. Normal distribution of CFTR mRNA was found in CF tissues while expression of CFTR protein was genotype specific, with ΔF508 homozygotes demonstrating no detectable protein and compound heterozygotes expressing decreased levels of normally distributed protein. Our data suggest mechanisms whereby defects in CFTR expression could lead to abnormal production of mucus in human lung.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Boat, T.F., Welsh, M.J. & Beaudet, A.L. Cystic fibrosis. In The Metabolic Basis of Inherited Disease (eds Scriver, C.R., Beaudet, A.L, Sly, W.S. & Valle, D.) 2649–2480 (McGraw-Hill, New York, 1989).

    Google Scholar 

  2. Nathanson, I. & Nadel, J.A. Movement of electrolytes and fluid across airways. Lung. 162, 125–137 (1984).

    Article  CAS  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.. 78, 1245–1252 (1986).

    Article  CAS  Google Scholar 

  4. Frizzell, R.A., Rechkemmer, G. & Shoemaker, R.L. Altered regulation of airway epithelial cell chloride channels in cystic fibrosis. Science 233, 558–560 (1986).

    Article  CAS  Google Scholar 

  5. Li, M. et al. AMP-dependent protein kinase opens chloride channels in normal but not cystic fibrosis airway epithelium. Nature 331, 358–360 (1988).

    Article  CAS  Google Scholar 

  6. Rommens, J.M. et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245, 1059–1065 (1989).

    Article  CAS  Google Scholar 

  7. Riordan, J.R. et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245, 1066–1073 (1989).

    Article  CAS  Google Scholar 

  8. Kerem, B.-S. et al. Identification of the cystic fibrosis gene: genetic analysis. Science 245, 1073–1080 (1989).

    Article  CAS  Google Scholar 

  9. Anderson, M.P. et al. Demonstration that CFTR is a chloride channel by alteration of its anion selectivity. Science 253, 202–205 (1991).

    Article  CAS  Google Scholar 

  10. Bear, C.E. et al. Purification and functional reconstitution of the cystic fibrosis trnasmembrane conductance regulator (CFTR). Cell 68, 809–818 (1992).

    Article  CAS  Google Scholar 

  11. Umeki, S. Primary mucociliary transport failure. Respiration. 54, 220–225 (1988).

    Article  CAS  Google Scholar 

  12. Katz, S.M. & Holsclaw, D.S. Ultrastructural features of respiratory cilia in cystic fibrosis. Am. J. clin. Pathol. 73, 682–685 (1980).

    Article  CAS  Google Scholar 

  13. Rutland, J. & Cole, P.J. Nasal mucociliary clearance and ciliary beat frewuency in cystic fibrosis compaired with sinusitis and bronchiectasis. Thorax 36, 654–658 (1981).

    Article  CAS  Google Scholar 

  14. Meyrick, B., Sturgess, J.M. & Reid, L. A reconstruction of the duct system and secretory tubules of the human bronchial submucosal gland. Thorax 24, 729 (1969).

    Article  CAS  Google Scholar 

  15. Phipps, R.J. The airway mucociliary system. Resp. Physiol. 23, 213–260 (1981).

    CAS  Google Scholar 

  16. Basbaum, C.B., Jany, B. & Finkbeiner, W.E. The serous cell. Ann. Rev. Physiol. 52, 97–113 (1990).

    Article  CAS  Google Scholar 

  17. Meyrick, B. & Reid, L. Ultrastructure of cells in the human bronchial submucosal glands. J. Anat. 107, 281–299 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Cohn, J.A., Melhus, O., Page, L.J., Dittrich, K.L. & Vigna, S.R. CFTR: development of high-affinity antibodies and localization in sweat gland. Biochem. Biophys. Res. Commun. 181, 36–43 (1991).

    Article  CAS  Google Scholar 

  19. Crawford, I. et al. Immunocytochemical localization of the cystic fibrosis gene product CFTR. Proc. natn. Acad. Sci. U.S.A. 88, 9262–9266 (1991).

    Article  CAS  Google Scholar 

  20. Marino, C.R., Matovcik, L.M., Gorelick, F.S. & Cohn, J.A. Localization of the cystic fibrosis transmembrane conductance regulator in pancreas. J. clin. Invest. 88, 712–716 (1991).

    Article  CAS  Google Scholar 

  21. Trapnell, B.C. et al. Expression of the cystic fibrosis transmembrane conductance regulator gene in the respiratory tract of normal individuals and individuals with cystic fibrosis. Proc. natn. Acad. Sci. U.S.A. 88, 6565–6569 (1991).

    Article  CAS  Google Scholar 

  22. Trezise, A.E.O. & Buchwald, M. In vivo cell-specific expression of the cystic fibrosis transmembrane conductance regulator. Nature 353, 434–437 (1991).

    Article  CAS  Google Scholar 

  23. Zeitlin, P.L. et al. CFTR protein expression in primary and cultured epitelia. Proc. natn. Acad. Sci. U.S.A. 89, 344–347 (1992).

    Article  CAS  Google Scholar 

  24. Rutten, A.A., Bruyntjes, J.P. & Ramaekers, F.C. Effect of cigarette smoke condensate and vitamin A depletion on keratin expression patterns in cultured hanster tracheal epithelium. Virchows. Archiv. B. Cell. Pathol. 56, 111–117 (1988).

    Article  CAS  Google Scholar 

  25. Oppenheimer, E.H. & Esterly, J.R. Pathology of cystic fibrosis review of the literature and comparison with 146 autopsied cases. In Perspectives in Pediatric Patholgy 2, (eds Rosenberg, H.S. & Bolande, R.P.) 241–278 (Year Book Medical Publishers, New York, 1975).

    Google Scholar 

  26. Yamaya, M., Finkbeiner, W.E. & Widdicombe, J.H. Ion transport by cultures of human tracheobronchial submucosal glands. Am. J. Physiol. 261, L485–490 (1991).

    CAS  PubMed  Google Scholar 

  27. Yamaya, M., Finkbeiner, W.E. & Widdicombe, J.H. Altered ion transport by tracheal glands in cystic fibrosis. Am. J Physiol. 261, L491–494 (1991b).

    CAS  PubMed  Google Scholar 

  28. Reid, L. Measurement of the bronchial mucous gland layer: A diognostic yardstick in chronic bronchitis. Thorax 15, 132 (1960).

    Article  CAS  Google Scholar 

  29. Snouwaert, J.N. et al. An animal model for cystic fibrosis made by gene targeting. Science 257, 1083–1088 (1992).

    Article  CAS  Google Scholar 

  30. Harkema, J.R., Mariassy, A., St. Gearge, J., Hyde, D.M. & Plopper, C.G. Epithelial Cells of the Conducting Airways: A Species Comparison. In Airway Epthelium: Physiology, Pathophysiology, and Pharmacology (eds Farmer, S.G. & Hay, D.W.P.) 3–39 (Marcel Dekker, New York, 1990).

    Google Scholar 

  31. Silva, P. et al. Mechanism of active chloride secretion by shark rectal gland: role of Na-K-ATPase in chloride transport. Am. J. Physiol. 233, 298–306 (1977).

    Google Scholar 

  32. Greger, R., Schlatter, E., Wang, F. & Forrest, J.N. Jr, Mechanism of NaCl Secretion in rectal gland tubules of spiny dogfish (Squalus acanthias). III. Effects of stimulation of secretion by cyclic AMP. Pflugers Arch. 402, 376–384 (1984).

    Article  CAS  Google Scholar 

  33. Thompson, I.G. & Mills, J.W. Chloride transport in gland of frog skin. Am. Physiol. Soc. 221–226 (1983).

  34. Quinton, P.M. Cystic fibrosis: a disease in electrolyte transport. FASEB J. 4, 2709–2717 (1990).

    Article  CAS  Google Scholar 

  35. Sato, K. et al. Roles of Ca and cAMP on Cl channel activity in cystic fibrosis sweat clear cells as studied by microsuperfusion and cell volume analysis. Adv. Exp. med. Biol. 290, 145–158 (1991).

    Article  CAS  Google Scholar 

  36. Martinez, J.R. Cellular mechanisms underlying the production of primary secretory fluid in salivary glands. Crit. Rev. Oral Biol. Med. 1, 67–78 (1990).

    Article  CAS  Google Scholar 

  37. Frizzell, R.A., Field, M. & Schultz, S.G. Sodium-coupled chloride transport by epithelial tissues. Am. J. Physiol. 236, 1–8 (1979).

    Article  Google Scholar 

  38. Greger, R., Schlatter, E. & Gogelein, H. Chloride channels in the luminal membrane of the rectal gland of the dogfish (Squalus acanthias). Pflugers Arch. 409, 114–121 (1987).

    Article  CAS  Google Scholar 

  39. Liedtke, C.M. Regulation of chloride transport in epithelia. An. Rev. Physiol. 51, 143–160 (1989).

    Article  CAS  Google Scholar 

  40. Leikauf, G.D., Ueki, I.F. & Nadel, J.A. Autonomic regulation of viscoelasticity of cat tracheal gland secretions. J. Appl. Physiol. 56, 426–430 (1984).

    Article  CAS  Google Scholar 

  41. Tam, P.Y. & Verdugo, P. Control of mucus hydration as a Donnan equilibrium process. Nature 292, 340–342 (1981).

    Article  CAS  Google Scholar 

  42. Verdugo, P., Langley, L., Aitken, M.L. & Villalon, M. Development of an in vitro model of primate cervical goblet cells. Biotheology 27, 465–470 (1990).

    Article  CAS  Google Scholar 

  43. Larsen, E.H. Chloride transport by high-resistance heterocellular epithelia. Physiol. Rev. 71, 235–283 (1991).

    Article  CAS  Google Scholar 

  44. Katz, U. & Scheffey, C. The voltage-dependent chloride current conductance of toad skin is localized to mitochondria-rich cells. Biochim. Biophys. Acta. 861, 480–482 (1986).

    Article  CAS  Google Scholar 

  45. Cheng, S.H. et al. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell. 63, 827–834 (1990).

    Article  CAS  Google Scholar 

  46. Kartner, N., Augustinas, O., Jensen, T.J., Naismith, A.L. & Riordan, J.R. Mislocalization of ΔF508 CFTR in cystic fibrosis sweat gland. Nature Genet. 1, 321–327 (1992).

    Article  CAS  Google Scholar 

  47. Cohn, J.A., Nairn, A.C., Marino, C.R., Melhus, O. & Kole, J. Characterization of the cystic fibrosis transmembrane conductance regulator in a colonocyte cell line. Proc. natn. Acad. Sci. U.S.A. 89, 2340–2344 (1992).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Engelhardt, J., Yankaskas, J., Ernst, S. et al. Submucosal glands are the predominant site of CFTR expression in the human bronchus. Nat Genet 2, 240–248 (1992). https://doi.org/10.1038/ng1192-240

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1192-240

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing