Skip to main content
NCBI home page
Thorax logoLink to Thorax
. 2004 Nov;59(11):992–996. doi: 10.1136/thx.2003.018879

Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium

P Burgel 1, J Nadel 1
PMCID: PMC1746853  PMID: 15516478

Abstract

The epithelial cells lining the airways serve protective functions. The "barrier function" of the epithelium protects the individual from damage by inhaled irritants. The epithelium produces mucins which become hydrated and form a viscoelastic gel which spreads over the epithelial surface. In healthy individuals inhaled foreign materials become entrapped in the mucus and are cleared by mucociliary transport and by coughing. In many chronic inflammatory airway diseases, however, excessive mucus is produced and is inadequately cleared, leading to mucous obstruction and infection. At present there is no specific treatment for hypersecretion. However, the discovery that an epidermal growth factor receptor (EGFR) cascade is involved in mucin production by a wide variety of stimuli suggests that blockade may provide specific treatment for hypersecretory diseases. EGFR pathways have also been implicated in the repair of damaged airway epithelium. The roles of EGFR in airway epithelial cell hypersecretion and epithelial damage and repair are reviewed and future potential treatments are suggested.

Full Text

The Full Text of this article is available as a PDF (120.6 KB).

Selected References

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

  1. Barrow R. E., Wang C. Z., Evans M. J., Herndon D. N. Growth factors accelerate epithelial repair in sheep trachea. Lung. 1993;171(6):335–344. doi: 10.1007/BF00165699. [DOI] [PubMed] [Google Scholar]
  2. Booth B. W., Adler K. B., Bonner J. C., Tournier F., Martin L. D. Interleukin-13 induces proliferation of human airway epithelial cells in vitro via a mechanism mediated by transforming growth factor-alpha. Am J Respir Cell Mol Biol. 2001 Dec;25(6):739–743. doi: 10.1165/ajrcmb.25.6.4659. [DOI] [PubMed] [Google Scholar]
  3. Burgel P. R., Escudier E., Coste A., Dao-Pick T., Ueki I. F., Takeyama K., Shim J. J., Murr A. H., Nadel J. A. Relation of epidermal growth factor receptor expression to goblet cell hyperplasia in nasal polyps. J Allergy Clin Immunol. 2000 Oct;106(4):705–712. doi: 10.1067/mai.2000.109823. [DOI] [PubMed] [Google Scholar]
  4. Burgel P. R., Lazarus S. C., Tam D. C., Ueki I. F., Atabai K., Birch M., Nadel J. A. Human eosinophils induce mucin production in airway epithelial cells via epidermal growth factor receptor activation. J Immunol. 2001 Nov 15;167(10):5948–5954. doi: 10.4049/jimmunol.167.10.5948. [DOI] [PubMed] [Google Scholar]
  5. Chokki Manabu, Yamamura Satoshi, Eguchi Hiroshi, Masegi Tsukio, Horiuchi Hideki, Tanabe Hirofumi, Kamimura Takashi, Yasuoka Susumu. Human airway trypsin-like protease increases mucin gene expression in airway epithelial cells. Am J Respir Cell Mol Biol. 2003 Sep 18;30(4):470–478. doi: 10.1165/rcmb.2003-0199OC. [DOI] [PubMed] [Google Scholar]
  6. Cohen S. Nobel lecture. Epidermal growth factor. Biosci Rep. 1986 Dec;6(12):1017–1028. doi: 10.1007/BF01141022. [DOI] [PubMed] [Google Scholar]
  7. Dong J., Opresko L. K., Dempsey P. J., Lauffenburger D. A., Coffey R. J., Wiley H. S. Metalloprotease-mediated ligand release regulates autocrine signaling through the epidermal growth factor receptor. Proc Natl Acad Sci U S A. 1999 May 25;96(11):6235–6240. doi: 10.1073/pnas.96.11.6235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Goldkorn T., Balaban N., Matsukuma K., Chea V., Gould R., Last J., Chan C., Chavez C. EGF-Receptor phosphorylation and signaling are targeted by H2O2 redox stress. Am J Respir Cell Mol Biol. 1998 Nov;19(5):786–798. doi: 10.1165/ajrcmb.19.5.3249. [DOI] [PubMed] [Google Scholar]
  9. Hackel P. O., Zwick E., Prenzel N., Ullrich A. Epidermal growth factor receptors: critical mediators of multiple receptor pathways. Curr Opin Cell Biol. 1999 Apr;11(2):184–189. doi: 10.1016/s0955-0674(99)80024-6. [DOI] [PubMed] [Google Scholar]
  10. Herbst Roy S., Bunn Paul A., Jr Targeting the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res. 2003 Dec 1;9(16 Pt 1):5813–5824. [PubMed] [Google Scholar]
  11. Inman M. Is there a place for anti-remodelling drugs in asthma which may not display immediate clinical efficacy? Eur Respir J. 2004 Jul;24(1):1–2. doi: 10.1183/09031936.04.00044304. [DOI] [PubMed] [Google Scholar]
  12. Kim J. S., McKinnis V. S., Nawrocki A., White S. R. Stimulation of migration and wound repair of guinea-pig airway epithelial cells in response to epidermal growth factor. Am J Respir Cell Mol Biol. 1998 Jan;18(1):66–74. doi: 10.1165/ajrcmb.18.1.2740. [DOI] [PubMed] [Google Scholar]
  13. Klapper L. N., Kirschbaum M. H., Sela M., Yarden Y. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res. 2000;77:25–79. [PubMed] [Google Scholar]
  14. Kohri K., Ueki I. F., Shim J. J., Burgel P. R., Oh Y. M., Tam D. C., Dao-Pick T., Nadel J. A. Pseudomonas aeruginosa induces MUC5AC production via epidermal growth factor receptor. Eur Respir J. 2002 Nov;20(5):1263–1270. doi: 10.1183/09031936.02.00001402. [DOI] [PubMed] [Google Scholar]
  15. Laitinen L. A., Heino M., Laitinen A., Kava T., Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis. 1985 Apr;131(4):599–606. doi: 10.1164/arrd.1985.131.4.599. [DOI] [PubMed] [Google Scholar]
  16. Lamblin G., Degroote S., Perini J. M., Delmotte P., Scharfman A., Davril M., Lo-Guidice J. M., Houdret N., Dumur V., Klein A. Human airway mucin glycosylation: a combinatory of carbohydrate determinants which vary in cystic fibrosis. Glycoconj J. 2001 Sep;18(9):661–684. doi: 10.1023/a:1020867221861. [DOI] [PubMed] [Google Scholar]
  17. Lemjabbar Hassan, Basbaum Carol. Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Nat Med. 2002 Jan;8(1):41–46. doi: 10.1038/nm0102-41. [DOI] [PubMed] [Google Scholar]
  18. Li J. D., Dohrman A. F., Gallup M., Miyata S., Gum J. R., Kim Y. S., Nadel J. A., Prince A., Basbaum C. B. Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):967–972. doi: 10.1073/pnas.94.3.967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Li J. D., Feng W., Gallup M., Kim J. H., Gum J., Kim Y., Basbaum C. Activation of NF-kappaB via a Src-dependent Ras-MAPK-pp90rsk pathway is required for Pseudomonas aeruginosa-induced mucin overproduction in epithelial cells. Proc Natl Acad Sci U S A. 1998 May 12;95(10):5718–5723. doi: 10.1073/pnas.95.10.5718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Madtes D. K., Busby H. K., Strandjord T. P., Clark J. G. Expression of transforming growth factor-alpha and epidermal growth factor receptor is increased following bleomycin-induced lung injury in rats. Am J Respir Cell Mol Biol. 1994 Nov;11(5):540–551. doi: 10.1165/ajrcmb.11.5.7524566. [DOI] [PubMed] [Google Scholar]
  21. Madtes D. K., Raines E. W., Sakariassen K. S., Assoian R. K., Sporn M. B., Bell G. I., Ross R. Induction of transforming growth factor-alpha in activated human alveolar macrophages. Cell. 1988 Apr 22;53(2):285–293. doi: 10.1016/0092-8674(88)90390-x. [DOI] [PubMed] [Google Scholar]
  22. Matthay M. A., Thiery J. P., Lafont F., Stampfer F., Boyer B. Transient effect of epidermal growth factor on the motility of an immortalized mammary epithelial cell line. J Cell Sci. 1993 Nov;106(Pt 3):869–878. doi: 10.1242/jcs.106.3.869. [DOI] [PubMed] [Google Scholar]
  23. Ordoñez C. L., Khashayar R., Wong H. H., Ferrando R., Wu R., Hyde D. M., Hotchkiss J. A., Zhang Y., Novikov A., Dolganov G. Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am J Respir Crit Care Med. 2001 Feb;163(2):517–523. doi: 10.1164/ajrccm.163.2.2004039. [DOI] [PubMed] [Google Scholar]
  24. Perrais Michaël, Pigny Pascal, Copin Marie-Christine, Aubert Jean-Pierre, Van Seuningen Isabelle. Induction of MUC2 and MUC5AC mucins by factors of the epidermal growth factor (EGF) family is mediated by EGF receptor/Ras/Raf/extracellular signal-regulated kinase cascade and Sp1. J Biol Chem. 2002 Jun 19;277(35):32258–32267. doi: 10.1074/jbc.M204862200. [DOI] [PubMed] [Google Scholar]
  25. Polosa R., Prosperini G., Leir S. H., Holgate S. T., Lackie P. M., Davies D. E. Expression of c-erbB receptors and ligands in human bronchial mucosa. Am J Respir Cell Mol Biol. 1999 May;20(5):914–923. doi: 10.1165/ajrcmb.20.5.3308. [DOI] [PubMed] [Google Scholar]
  26. Prenzel N., Zwick E., Daub H., Leserer M., Abraham R., Wallasch C., Ullrich A. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature. 1999 Dec 23;402(6764):884–888. doi: 10.1038/47260. [DOI] [PubMed] [Google Scholar]
  27. Puddicombe S. M., Polosa R., Richter A., Krishna M. T., Howarth P. H., Holgate S. T., Davies D. E. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J. 2000 Jul;14(10):1362–1374. doi: 10.1096/fj.14.10.1362. [DOI] [PubMed] [Google Scholar]
  28. Richter Audrey, O'Donnell Rory A., Powell Robert M., Sanders Michael W., Holgate Stephen T., Djukanović Ratko, Davies Donna E. Autocrine ligands for the epidermal growth factor receptor mediate interleukin-8 release from bronchial epithelial cells in response to cigarette smoke. Am J Respir Cell Mol Biol. 2002 Jul;27(1):85–90. doi: 10.1165/ajrcmb.27.1.4789. [DOI] [PubMed] [Google Scholar]
  29. Shao Matt X. G., Ueki Iris F., Nadel Jay A. Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci U S A. 2003 Sep 12;100(20):11618–11623. doi: 10.1073/pnas.1534804100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sharma P., Dudus L., Nielsen P. A., Clausen H., Yankaskas J. R., Hollingsworth M. A., Engelhardt J. F. MUC5B and MUC7 are differentially expressed in mucous and serous cells of submucosal glands in human bronchial airways. Am J Respir Cell Mol Biol. 1998 Jul;19(1):30–37. doi: 10.1165/ajrcmb.19.1.3054. [DOI] [PubMed] [Google Scholar]
  31. Sinha Atul, Nightingale Jeremy, West Kevin P., Berlanga-Acosta Jorge, Playford Raymond J. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med. 2003 Jul 24;349(4):350–357. doi: 10.1056/NEJMoa013136. [DOI] [PubMed] [Google Scholar]
  32. Stoll S., Garner W., Elder J. Heparin-binding ligands mediate autocrine epidermal growth factor receptor activation In skin organ culture. J Clin Invest. 1997 Sep 1;100(5):1271–1281. doi: 10.1172/JCI119641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Takeyama K., Dabbagh K., Jeong Shim J., Dao-Pick T., Ueki I. F., Nadel J. A. Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: role of neutrophils. J Immunol. 2000 Feb 1;164(3):1546–1552. doi: 10.4049/jimmunol.164.3.1546. [DOI] [PubMed] [Google Scholar]
  34. Takeyama K., Dabbagh K., Lee H. M., Agustí C., Lausier J. A., Ueki I. F., Grattan K. M., Nadel J. A. Epidermal growth factor system regulates mucin production in airways. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3081–3086. doi: 10.1073/pnas.96.6.3081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Takeyama K., Fahy J. V., Nadel J. A. Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am J Respir Crit Care Med. 2001 Feb;163(2):511–516. doi: 10.1164/ajrccm.163.2.2001038. [DOI] [PubMed] [Google Scholar]
  36. Van Winkle L. S., Isaac J. M., Plopper C. G. Distribution of epidermal growth factor receptor and ligands during bronchiolar epithelial repair from naphthalene-induced Clara cell injury in the mouse. Am J Pathol. 1997 Aug;151(2):443–459. [PMC free article] [PubMed] [Google Scholar]
  37. Vestbo Jørgen. Epidemiological studies in mucus hypersecretion. Novartis Found Symp. 2002;248:3-12; discussion 12-9, 277-82. [PubMed] [Google Scholar]
  38. White S. R., Dorscheid D. R., Rabe K. F., Wojcik K. R., Hamann K. J. Role of very late adhesion integrins in mediating repair of human airway epithelial cell monolayers after mechanical injury. Am J Respir Cell Mol Biol. 1999 Apr;20(4):787–796. doi: 10.1165/ajrcmb.20.4.3318. [DOI] [PubMed] [Google Scholar]
  39. Wong D. T., Weller P. F., Galli S. J., Elovic A., Rand T. H., Gallagher G. T., Chiang T., Chou M. Y., Matossian K., McBride J. Human eosinophils express transforming growth factor alpha. J Exp Med. 1990 Sep 1;172(3):673–681. doi: 10.1084/jem.172.3.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zhang L., Rice A. B., Adler K., Sannes P., Martin L., Gladwell W., Koo J. S., Gray T. E., Bonner J. C. Vanadium stimulates human bronchial epithelial cells to produce heparin-binding epidermal growth factor-like growth factor: a mitogen for lung fibroblasts. Am J Respir Cell Mol Biol. 2001 Feb;24(2):123–131. doi: 10.1165/ajrcmb.24.2.4096. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES