Skip to main content
NCBI home page
Thorax logoLink to Thorax
. 2004 Dec;59(12):1032–1040. doi: 10.1136/thx.2004.028043

Expression of ErbB receptors and mucins in the airways of long term current smokers

R O'Donnell 1, A Richter 1, J Ward 1, G Angco 1, A Mehta 1, K Rousseau 1, D Swallow 1, S Holgate 1, R Djukanovic 1, D Davies 1, S Wilson 1
PMCID: PMC1746902  PMID: 15563701

Abstract

Background: Airway epithelial goblet cell hyperplasia is known to occur in chronic smokers. Although the epidermal growth factor receptor has been implicated in this process, neither ErbB receptor expression nor the mucosecretory phenotype of the epithelium have been characterised in current smokers.

Methods: Bronchial biopsies obtained from non-smokers (n = 10) and current smokers, with or without chronic obstructive pulmonary disease (n = 51), were examined immunohistochemically to measure the expression of epidermal growth factor receptor, ErbB2, ErbB3, ErbB4 and mucin subtypes (MUC2, MUC5AC and MUC5B) in the bronchial epithelium. The results were correlated with neutrophil counts measured in the airway wall and induced sputum.

Results: Epidermal growth factor receptor, ErbB3 and MUC5AC expression, in addition to PAS staining, were significantly increased in all smokers compared with non-smokers, irrespective of the presence of chronic obstructive pulmonary disease. MUC5AC expression was significantly associated with both PAS staining and ErbB3 expression; no correlation was observed between either mucin or ErbB receptor expression and neutrophil counts.

Conclusions: The results suggest that long term current smoking induces enhanced epidermal growth factor receptor, ErbB3, and MUC5AC expression in vivo; these increases are not associated with the presence of neutrophilic inflammation. ErbB receptors may contribute to epithelial responses to cigarette smoke.

Full Text

The Full Text of this article is available as a PDF (287.8 KB).

Selected References

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

  1. Alroy I., Yarden Y. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett. 1997 Jun 23;410(1):83–86. doi: 10.1016/s0014-5793(97)00412-2. [DOI] [PubMed] [Google Scholar]
  2. Amishima M., Munakata M., Nasuhara Y., Sato A., Takahashi T., Homma Y., Kawakami Y. Expression of epidermal growth factor and epidermal growth factor receptor immunoreactivity in the asthmatic human airway. Am J Respir Crit Care Med. 1998 Jun;157(6 Pt 1):1907–1912. doi: 10.1164/ajrccm.157.6.9609040. [DOI] [PubMed] [Google Scholar]
  3. Audie J. P., Janin A., Porchet N., Copin M. C., Gosselin B., Aubert J. P. Expression of human mucin genes in respiratory, digestive, and reproductive tracts ascertained by in situ hybridization. J Histochem Cytochem. 1993 Oct;41(10):1479–1485. doi: 10.1177/41.10.8245407. [DOI] [PubMed] [Google Scholar]
  4. Bara J., Chastre E., Mahiou J., Singh R. L., Forgue-Lafitte M. E., Hollande E., Godeau F. Gastric M1 mucin, an early oncofetal marker of colon carcinogenesis, is encoded by the MUC5AC gene. Int J Cancer. 1998 Mar 2;75(5):767–773. doi: 10.1002/(sici)1097-0215(19980302)75:5<767::aid-ijc17>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  5. Barsky S. H., Roth M. D., Kleerup E. C., Simmons M., Tashkin D. P. Histopathologic and molecular alterations in bronchial epithelium in habitual smokers of marijuana, cocaine, and/or tobacco. J Natl Cancer Inst. 1998 Aug 19;90(16):1198–1205. doi: 10.1093/jnci/90.16.1198. [DOI] [PubMed] [Google Scholar]
  6. Britten K. M., Howarth P. H., Roche W. R. Immunohistochemistry on resin sections: a comparison of resin embedding techniques for small mucosal biopsies. Biotech Histochem. 1993 Sep;68(5):271–280. doi: 10.3109/10520299309105629. [DOI] [PubMed] [Google Scholar]
  7. Chen Yin, Thai Philip, Zhao Yu-Hua, Ho Ye-Shih, DeSouza Mary M., Wu Reen. Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J Biol Chem. 2003 Mar 6;278(19):17036–17043. doi: 10.1074/jbc.M210429200. [DOI] [PubMed] [Google Scholar]
  8. Chen Yin, Zhao Yu Hua, Kalaslavadi Tejas Baba, Hamati Edward, Nehrke Keith, Le Anh Dao, Ann David K., Wu Reen. Genome-wide search and identification of a novel gel-forming mucin MUC19/Muc19 in glandular tissues. Am J Respir Cell Mol Biol. 2003 Jul 25;30(2):155–165. doi: 10.1165/rcmb.2003-0103OC. [DOI] [PubMed] [Google Scholar]
  9. Cosio M. G., Hale K. A., Niewoehner D. E. Morphologic and morphometric effects of prolonged cigarette smoking on the small airways. Am Rev Respir Dis. 1980 Aug;122(2):265–221. doi: 10.1164/arrd.1980.122.2.265. [DOI] [PubMed] [Google Scholar]
  10. Cosio M., Ghezzo H., Hogg J. C., Corbin R., Loveland M., Dosman J., Macklem P. T. The relations between structural changes in small airways and pulmonary-function tests. N Engl J Med. 1978 Jun 8;298(23):1277–1281. doi: 10.1056/NEJM197806082982303. [DOI] [PubMed] [Google Scholar]
  11. Davies D. E., Polosa R., Puddicombe S. M., Richter A., Holgate S. T. The epidermal growth factor receptor and its ligand family: their potential role in repair and remodelling in asthma. Allergy. 1999 Aug;54(8):771–783. [PubMed] [Google Scholar]
  12. Graus-Porta D., Beerli R. R., Daly J. M., Hynes N. E. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997 Apr 1;16(7):1647–1655. doi: 10.1093/emboj/16.7.1647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Groneberg D. A., Eynott P. R., Lim S., Oates T., Wu R., Carlstedt I., Roberts P., McCann B., Nicholson A. G., Harrison B. D. Expression of respiratory mucins in fatal status asthmaticus and mild asthma. Histopathology. 2002 Apr;40(4):367–373. doi: 10.1046/j.1365-2559.2002.01378.x. [DOI] [PubMed] [Google Scholar]
  14. Hale K. A., Ewing S. L., Gosnell B. A., Niewoehner D. E. Lung disease in long-term cigarette smokers with and without chronic air-flow obstruction. Am Rev Respir Dis. 1984 Nov;130(5):716–721. doi: 10.1164/arrd.1984.130.5.716. [DOI] [PubMed] [Google Scholar]
  15. Hardie W. D., Bejarano P. A., Miller M. A., Yankaskas J. R., Ritter J. H., Whitsett J. A., Korfhagen T. R. Immunolocalization of transforming growth factor alpha and epidermal growth factor receptor in lungs of patients with cystic fibrosis. Pediatr Dev Pathol. 1999 Sep-Oct;2(5):415–423. doi: 10.1007/s100249900144. [DOI] [PubMed] [Google Scholar]
  16. Hill A. T., Bayley D., Stockley R. A. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am J Respir Crit Care Med. 1999 Sep;160(3):893–898. doi: 10.1164/ajrccm.160.3.9901091. [DOI] [PubMed] [Google Scholar]
  17. Hogg J. C., Macklem P. T., Thurlbeck W. M. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med. 1968 Jun 20;278(25):1355–1360. doi: 10.1056/NEJM196806202782501. [DOI] [PubMed] [Google Scholar]
  18. Jones P. W., Quirk F. H., Baveystock C. M., Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis. 1992 Jun;145(6):1321–1327. doi: 10.1164/ajrccm/145.6.1321. [DOI] [PubMed] [Google Scholar]
  19. Keatings V. M., Jatakanon A., Worsdell Y. M., Barnes P. J. Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med. 1997 Feb;155(2):542–548. doi: 10.1164/ajrccm.155.2.9032192. [DOI] [PubMed] [Google Scholar]
  20. Levine S. J., Larivée P., Logun C., Angus C. W., Ognibene F. P., Shelhamer J. H. Tumor necrosis factor-alpha induces mucin hypersecretion and MUC-2 gene expression by human airway epithelial cells. Am J Respir Cell Mol Biol. 1995 Feb;12(2):196–204. doi: 10.1165/ajrcmb.12.2.7865217. [DOI] [PubMed] [Google Scholar]
  21. Louahed J., Toda M., Jen J., Hamid Q., Renauld J. C., Levitt R. C., Nicolaides N. C. Interleukin-9 upregulates mucus expression in the airways. Am J Respir Cell Mol Biol. 2000 Jun;22(6):649–656. doi: 10.1165/ajrcmb.22.6.3927. [DOI] [PubMed] [Google Scholar]
  22. Louis R., Lau L. C., Bron A. O., Roldaan A. C., Radermecker M., Djukanović R. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med. 2000 Jan;161(1):9–16. doi: 10.1164/ajrccm.161.1.9802048. [DOI] [PubMed] [Google Scholar]
  23. Louis R., Shute J., Goldring K., Perks B., Lau L. C., Radermecker M., Djukanovic R. The effect of processing on inflammatory markers in induced sputum. Eur Respir J. 1999 Mar;13(3):660–667. doi: 10.1183/09031936.99.13366099. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Mitchell R. S., Stanford R. E., Johnson J. M., Silvers G. W., Dart G., George M. S. The morphologic features of the bronchi, bronchioles, and alveoli in chronic airway obstruction: a clinicopathologic study. Am Rev Respir Dis. 1976 Jul;114(1):137–145. doi: 10.1164/arrd.1976.114.1.137. [DOI] [PubMed] [Google Scholar]
  26. Morgan Wayne J., Crain Ellen F., Gruchalla Rebecca S., O'Connor George T., Kattan Meyer, Evans Richard, 3rd, Stout James, Malindzak George, Smartt Ernestine, Plaut Marshall. Results of a home-based environmental intervention among urban children with asthma. N Engl J Med. 2004 Sep 9;351(11):1068–1080. doi: 10.1056/NEJMoa032097. [DOI] [PubMed] [Google Scholar]
  27. Nagai A., West W. W., Thurlbeck W. M. The National Institutes of Health Intermittent Positive-Pressure Breathing trial: pathology studies. II. Correlation between morphologic findings, clinical findings, and evidence of expiratory air-flow obstruction. Am Rev Respir Dis. 1985 Nov;132(5):946–953. doi: 10.1164/arrd.1985.132.5.946. [DOI] [PubMed] [Google Scholar]
  28. Niewoehner D. E., Kleinerman J., Rice D. B. Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med. 1974 Oct 10;291(15):755–758. doi: 10.1056/NEJM197410102911503. [DOI] [PubMed] [Google Scholar]
  29. O'Donnell R. A., Peebles C., Ward J. A., Daraker A., Angco G., Broberg P., Pierrou S., Lund J., Holgate S. T., Davies D. E. Relationship between peripheral airway dysfunction, airway obstruction, and neutrophilic inflammation in COPD. Thorax. 2004 Oct;59(10):837–842. doi: 10.1136/thx.2003.019349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Peleman R. A., Rytilä P. H., Kips J. C., Joos G. F., Pauwels R. A. The cellular composition of induced sputum in chronic obstructive pulmonary disease. Eur Respir J. 1999 Apr;13(4):839–843. doi: 10.1034/j.1399-3003.1999.13d24.x. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Polosa Riccardo, Puddicombe Sarah M., Krishna M. Thirumala, Tuck Angela B., Howarth Peter H., Holgate Stephen T., Davies Donna E. Expression of c-erbB receptors and ligands in the bronchial epithelium of asthmatic subjects. J Allergy Clin Immunol. 2002 Jan;109(1):75–81. doi: 10.1067/mai.2002.120274. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Pulford K. A., Erber W. N., Crick J. A., Olsson I., Micklem K. J., Gatter K. C., Mason D. Y. Use of monoclonal antibody against human neutrophil elastase in normal and leukaemic myeloid cells. J Clin Pathol. 1988 Aug;41(8):853–860. doi: 10.1136/jcp.41.8.853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. 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]
  36. Rogers D. F. Airway goblet cells: responsive and adaptable front-line defenders. Eur Respir J. 1994 Sep;7(9):1690–1706. [PubMed] [Google Scholar]
  37. Rousseau K., Wickstrom C., Whitehouse D. B., Carlstedt I., Swallow D. M. New monoclonal antibodies to non-glycosylated domains of the secreted mucins MUC5B and MUC7. Hybrid Hybridomics. 2003 Oct;22(5):293–299. doi: 10.1089/153685903322538818. [DOI] [PubMed] [Google Scholar]
  38. Saetta M., Turato G., Baraldo S., Zanin A., Braccioni F., Mapp C. E., Maestrelli P., Cavallesco G., Papi A., Fabbri L. M. Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):1016–1021. doi: 10.1164/ajrccm.161.3.9907080. [DOI] [PubMed] [Google Scholar]
  39. Selvaggi Giovanni, Scagliotti Giorgio V., Torri Valter, Novello Silvia, Leonardo Eugenio, Cappia Susanna, Mossetti Claudio, Ardissone Francesco, Lausi Paolo, Borasio Piero. HER-2/neu overexpression in patients with radically resected nonsmall cell lung carcinoma. Impact on long-term survival. Cancer. 2002 May 15;94(10):2669–2674. doi: 10.1002/cncr.10531. [DOI] [PubMed] [Google Scholar]
  40. Srinivasan R., Poulsom R., Hurst H. C., Gullick W. J. Expression of the c-erbB-4/HER4 protein and mRNA in normal human fetal and adult tissues and in a survey of nine solid tumour types. J Pathol. 1998 Jul;185(3):236–245. doi: 10.1002/(SICI)1096-9896(199807)185:3<236::AID-PATH118>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  41. 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]
  42. 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]
  43. 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]
  44. Xing P. X., Prenzoska J., Layton G. T., Devine P. L., McKenzie I. F. Second-generation monoclonal antibodies to intestinal MUC2 peptide reactive with colon cancer. J Natl Cancer Inst. 1992 May 6;84(9):699–703. doi: 10.1093/jnci/84.9.699. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES