Role of Epidermal Growth Factor Receptor Cascade in Airway Epithelial Regulation of Mucus Production

  • Nadel  Jay
Part of the Allergy Frontiers book series (ALLERGY, volume 2)


The airways form an interface between the host and the environment. The lungs serve the function of gas exchange, and the airways connect the external environment with the lungs, where gas exchange occurs. During inspiration, a wide variety of microbes (e.g., bacteria, viruses) and irritants (e.g., cigarette smoke) deposit on the airway epithelial surface. The epithelium contains an “early warning system” for immediate responses to these particulate invaders, known as “innate immune responses”. Normally, exposure to these inhaled invaders occurs without symptoms or altered function, but in chronic airway diseases, exaggerated responses occur, leading to impaired function and death. Mucous hypersecretion is a major constituent of these disease states. This chapter focuses on mucins, the different effects of hypersecretion in large conducting airways vs small airways and the possible roles of hypersecretion in chronic airway diseases.

Importantly, the molecular, cellular, and physiologic mechanisms of mucin overproduction are described in detail. This includes a signaling cascade involving receptors that signal deposition of foreign particulates (especially the Toll-Like Receptors). Their activation is transmitted via a signaling cascade to activate the Epidermal Growth Factor Receptors (EGFR), whose phosphorylation leads to a series of defensive cellular responses, including mucin production.

The chapter ends with the present state of the art and future directions. It is suggested that inhibition of the EGFR cascade could provide novel therapy for mucous hypersecretion.


Respir Crit Airway Epithelium Peripheral Airway Mucin Production Human Neutrophil Elastase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Richter A, O'Donnell RA, Powell RM, Sanders MW, Holgate ST, Djukanovic R, Davies DE (2002) 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 27:85–90PubMedGoogle Scholar
  2. 2.
    Bals R, Hiemstra PS (2004) Innate immunity in the lung: how epithelial cells fight against respiratory pathogens. Eur Respir J 23:327–333PubMedCrossRefGoogle Scholar
  3. 3.
    Widdicombe JG (1995) Neurophysiology of the cough reflex. Eur Respir J 8:1193–1202PubMedCrossRefGoogle Scholar
  4. 4.
    Knowles MR, Boucher RC (2002) Mucus clearance as a primary innate defense mechanism for mammalian airways. J Clin Invest 109:571–577PubMedGoogle Scholar
  5. 5.
    Takeyama K, Dabbagh K, Lee HM, Agusti C, Lausier JA, Ueki IF, Grattan KM, Nadel JA (1999) Epidermal growth factor system regulates mucin production in airways. Proc Natl Acad Sci USA 96:3081–3086PubMedCrossRefGoogle Scholar
  6. 6.
    Nakanaga T, Nadel JA, Ueki IF, Koff JL, Shao MX (2007) Regulation of interleukin-8 via an airway epithelial signaling cascade. Am J Physiol Lung Cell Mol Physiol 292:L1289–1296PubMedCrossRefGoogle Scholar
  7. 7.
    Sorensen OE, Thapa DR, Rosenthal A, Liu L, Roberts AA, Ganz T (2005) Differential regulation of beta-defensin expression in human skin by microbial stimuli. J Immunol 174:4870–4879PubMedGoogle Scholar
  8. 8.
    Tjabringa GS, Aarbiou J, Ninaber DK, Drijfhout JW, Sorensen OE, Borregaard N, Rabe KF, Hiemstra PS (2003) The antimicrobial peptide LL-37 activates innate immunity at the airway epithelial surface by transactivation of the epidermal growth factor receptor. J Immunol 171:6690–6696PubMedGoogle Scholar
  9. 9.
    Matthay MA, Thiery JP, Lafont F, Stampfer F, Boyer B (1993) Transient effect of epidermal growth factor on the motility of an immortalized mammary epithelial cell line. J Cell Sci 106 (Pt 3):869–878PubMedGoogle Scholar
  10. 10.
    Puddicombe SM, Polosa R, Richter A, Krishna MT, Howarth PH, Holgate ST, Davies DE (2000) Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J 14:1362–1374PubMedCrossRefGoogle Scholar
  11. 11.
    Koff JL, Shao MX, Kim S, Ueki IF, Nadel JA (2006) Pseudomonas lipopolysaccharide accelerates wound repair via activation of a novel epithelial cell signaling cascade. J Immunol 177:8693–8700PubMedGoogle Scholar
  12. 12.
    Rose MC, Voynow JA (2006) Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev 86:245–278PubMedCrossRefGoogle Scholar
  13. 13.
    Andrianifahanana M, Moniaux N, Batra SK (2006) Regulation of mucin expression: Mechanistic aspects and implications for cancer and inflammatory diseases. Biochim Biophys Acta 1765:189–222PubMedGoogle Scholar
  14. 14.
    Thornton DJ, Sheehan JK (2004) From mucins to mucus. Toward a more coherent understanding of this essential barrier. Proc Am Thorac Soc 1:54–61PubMedCrossRefGoogle Scholar
  15. 15.
    Williams OW, Sharafkhaneh A, Kim V, Dickey BF, Evans CM (2006) Airway mucus: From production to secretion. Am J Respir Cell Mol Biol 34:527–536PubMedCrossRefGoogle Scholar
  16. 16.
    Hays SR, Fahy JV (2006) Characterizing mucous cell remodeling in cystic fibrosis: relationship to neutrophils. Am J Respir Crit Care Med 174:1018–1024PubMedCrossRefGoogle Scholar
  17. 17.
    Ordonez CL, Khashayar R, Wong HH, Ferrando R, Wu R, Hyde DM, Hotchkiss JA, Zhang Y, Novikov A, Dolganov G, Fahy JV (2001) Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am J Respir Crit Care Med 163:517–523PubMedGoogle Scholar
  18. 18.
    Burgel PR, Montani D, Danel C, Dusser DJ, Nadel JA (2007) A morphometric study of mucins and small airway plugging in cystic fibrosis. Thorax 62:153–161PubMedCrossRefGoogle Scholar
  19. 19.
    Shao MX, Nakanaga T, Nadel JA (2004) Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCIH292) cells. Am J Physiol Lung Cell Mol Physiol 287:L420–427PubMedCrossRefGoogle Scholar
  20. 20.
    Borchers MT, Wert SE, Leikauf GD (1998) Acrolein-induced MUC5ac expression in rat airways. Am J Physiol 274:L573–581PubMedGoogle Scholar
  21. 21.
    Verdugo P (1990) Goblet cells secretion and mucogenesis. Annu Rev Physiol 52:157–176PubMedCrossRefGoogle Scholar
  22. 22.
    Hogg JC (2004) Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet 364:709–721PubMedCrossRefGoogle Scholar
  23. 23.
    Dunnill MS (1960) The pathology of asthma with special reference to changes in the bronchial mucosa. J Clin Pathol 13:27–33PubMedCrossRefGoogle Scholar
  24. 24.
    Groneberg DA, Eynott PR, Lim S, Oates T, Wu R, Carlstedt I, Roberts P, McCann B, Nicholson AG, Harrison BD, Chung KF (2002) Expression of respiratory mucins in fatal status asthmaticus and mild asthma. Histopathology 40:367–373PubMedCrossRefGoogle Scholar
  25. 25.
    Kuyper LM, Pare PD, Hogg JC, Lambert RK, Ionescu D, Woods R, Bai TR (2003) Characterization of airway plugging in fatal asthma. Am J Med 115:6–11PubMedCrossRefGoogle Scholar
  26. 26.
    Shimura S, Andoh Y, Haraguchi M, Shirato K (1996) Continuity of airway goblet cells and intraluminal mucus in the airways of patients with bronchial asthma. Eur Respir J 9:1395–1401PubMedCrossRefGoogle Scholar
  27. 27.
    Zaas AK, Schwartz DA (2005) Innate immunity and the lung: defense at the interface between host and environment. Trends Cardiovasc Med 15:195–202PubMedCrossRefGoogle Scholar
  28. 28.
    Gibson RL, Burns JL, Ramsey BW (2003) Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 168:901–951CrossRefGoogle Scholar
  29. 29.
    Rosell A, Monso E, Soler N, Torres F, Angrill J, Riise G, Zalacain R, Morera J, Torres A (2005) Microbiologic determinants of exacerbations in chronic obstructive pulmonary disease. Arch Intern Med 165:891–897PubMedCrossRefGoogle Scholar
  30. 30.
    Takeyama K, Fahy JV, Nadel JA (2001) Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am J Respir Crit Care Med 163:511–516PubMedGoogle Scholar
  31. 31.
    Openshaw PJ, Turner-Warwick M (1989) Observations on sputum production in patients with variable airflow obstruction; implications for the diagnosis of asthma and chronic bronchitis. Respir Med 83:25–31PubMedCrossRefGoogle Scholar
  32. 32.
    Lange P, Parner J, Vestbo J, Schnohr P, Jensen G (1998) A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 339:1194–1200PubMedCrossRefGoogle Scholar
  33. 33.
    Aikawa T, Shimura S, Sasaki H, Ebina M, Takishima T (1992) Marked goblet cell hyperplasia with mucus accumulation in the airways of patients who died of severe acute asthma attack. Chest 101:916–921PubMedCrossRefGoogle Scholar
  34. 34.
    Nadel JA (2007) Innate immune mucin production via epithelial cell surface signaling: relationship to allergic disease. Curr Opin Allergy Clin Immunol 7:57–62PubMedCrossRefGoogle Scholar
  35. 35.
    Baggiolini M, Loetscher P, Moser B (1995) Interleukin-8 and the chemokine family. Int J Immunopharmacol 17:103–108PubMedCrossRefGoogle Scholar
  36. 36.
    Bousquet J, Chanez P, Lacoste JY, Barneon G, Ghavanian N, Enander I, Venge P, Ahlstedt S, Simony-Lafontaine J, Godard P, et al. (1990) Eosinophilic inflammation in asthma. N Engl J Med 323:1033–1039PubMedGoogle Scholar
  37. 37.
    Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, Corrigan C, Durham SR, Kay AB (1992) Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 326:298–304PubMedGoogle Scholar
  38. 38.
    Sur S, Crotty TB, Kephart GM, Hyma BA, Colby TV, Reed CE, Hunt LW, Gleich GJ (1993) Sudden-onset fatal asthma. A distinct entity with few eosinophils and relatively more neutrophils in the airway submucosa. Am Rev Respir Dis 148:713–719PubMedGoogle Scholar
  39. 39.
    Ordonez CL, Shaughnessy TE, Matthay MA, Fahy JV (2000) Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma: Clinical and biologic significance. Am J Respir Crit Care Med 161:1185–1190PubMedGoogle Scholar
  40. 40.
    Lamblin C, Gosset P, Tillie-Leblond I, Saulnier F, Marquette CH, Wallaert B, Tonnel AB (1998) Bronchial neutrophilia in patients with noninfectious status asthmaticus. Am J Respir Crit Care Med 157:394–402PubMedGoogle Scholar
  41. 41.
    Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD, Martin RJ (1997) Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 156:737–743PubMedGoogle Scholar
  42. 42.
    Vignola AM, Bonanno A, Mirabella A, Riccobono L, Mirabella F, Profita M, Bellia V, Bousquet J, Bonsignore G (1998) Increased levels of elastase and alpha1-antitrypsin in sputum of asthmatic patients. Am J Respir Crit Care Med 157:505–511PubMedGoogle Scholar
  43. 43.
    Shao MX, Nadel JA (2005) Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-alpha-converting enzyme. J Immunol 175:4009–4016PubMedGoogle Scholar
  44. 44.
    Desseyn JL, Aubert JP, Van Seuningen I, Porchet N, Laine A (1997) Genomic organization of the 3' region of the human mucin gene MUC5B. J Biol Chem 272:16873–16883PubMedCrossRefGoogle Scholar
  45. 45.
    Gum JRJ, Hicks JW, Toribara NW, Siddiki B, Kim YS (1994) Molecular cloning of human intestinal mucin (MUC2) cDNA. Identification of the amino terminus and overall sequence similarity to prepro-von Willebrand factor. J Biol Chem 269:2440–2446PubMedGoogle Scholar
  46. 46.
    Li D, Gallup M, Fan N, Szymkowski DE, Basbaum CB (1998) Cloning of the amino-terminal and 5'-flanking region of the human MUC5AC mucin gene and transcriptional up-regulation by bacterial exoproducts. J Biol Chem 273:6812–6820PubMedCrossRefGoogle Scholar
  47. 47.
    Meezaman D, Charles P, Daskal E, Polymeropoulos MH, Martin BM, Rose MC (1994) Cloning and analysis of cDNA encoding a major airway glycoprotein, human tracheobronchial mucin (MUC5). J Biol Chem 269:12932–12939PubMedGoogle Scholar
  48. 48.
    Voynow JA, Young LR, Wang Y, Horger T, Rose MC, Fischer BM (1999) Neutrophil elastase increases MUC5AC mRNA and protein expression in respiratory epithelial cells. Am J Physiol Lung Cell Mol Physiol 276:L835–L843Google Scholar
  49. 49.
    Scharfman A, Van Brussel E, Houdret N, Lamblin G, Roussel P (1996) Interactions between glycoconjugates from human respiratory airways and Pseudomonas aeruginosa. Am J Respir Crit Care Med 154:S163–S169PubMedGoogle Scholar
  50. 50.
    Lou YP, Takeyama K, Grattan KM, Lausier JA, Ueki IF, Agusti C, Nadel JA (1998) Platelet-activating factor induces goblet cell hyperplasia and mucin gene expression in airways. Am J Respir Crit Care Med 157:1927–1934PubMedGoogle Scholar
  51. 51.
    Guzman K, Gray TE, Yoon JH, Nettesheim P (1996) Quantitation of mucin RNA by PCR reveals induction of both MUC2 and MUC5AC mRNA levels by retinoids. Am J Physiol 271:L1023–L1028PubMedGoogle Scholar
  52. 52.
    Harkema JR, Hotchkiss JA (1993) Ozone- and endotoxin-induced mucous cell metaplasias in rat airway epithelium: novel animal models to study toxicant-induced epithelial transformation in airways. Toxicol Lett 68:251–263PubMedCrossRefGoogle Scholar
  53. 53.
    Jany B, Gallup M, Tsuda T, Basbaum C (1991) Mucin gene expression in rat airways following infection and irritation. Biochem Biophys Res Commun 181:1–8PubMedCrossRefGoogle Scholar
  54. 54.
    Dohrman A, Miyata S, Gallup M, Li JD, Chapelin C, Coste A, Escudier E, Nadel J, Basbaum C (1998) Mucin gene (MUC 2 and MUC 5AC) upregulation by Gram-positive and Gram-negative bacteria. Biochim Biophys Acta 1406:251–259PubMedGoogle Scholar
  55. 55.
    Li JD, Dohrman AF, Gallup M, Miyata S, Gum JR, Kim SK, Nadel JA, Prince A, Basbaum C (1997) Transcriptional activation of mucin by Pseudomonas aeruginosa lipopolysaccharide in the pathogenesis of cystic fibrosis lung disease. Proc Natl Acad Sci USA 94:967–972PubMedCrossRefGoogle Scholar
  56. 56.
    Li JD, Feng W, Gallup M, Kim JH, Gum J, Kim Y, Basbaum C (1998) 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 USA 95:5718–5723PubMedCrossRefGoogle Scholar
  57. 57.
    Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983PubMedCrossRefGoogle Scholar
  58. 58.
    Medzhitov R, Preston-Hurlburt P, Janeway CA, Jr. (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397PubMedCrossRefGoogle Scholar
  59. 59.
    Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088PubMedCrossRefGoogle Scholar
  60. 60.
    Ruocco S, Lallemand A, Tournier JM, Gaillard D (1996) Expression and localization of epidermal growth factor, transforming growth factor-alpha, and localization of their common receptor in fetal human lung development. Pediatr Res 39:448–455PubMedCrossRefGoogle Scholar
  61. 61.
    Hendler FJ, Ozanne BW (1984) Human squamous cell lung cancers express increased epidermal growth factor receptors. J Clin Invest 74:647–651PubMedCrossRefGoogle Scholar
  62. 62.
    Amishima M, Munakata M, Nasuhara Y, Sato A, Takahashi T, Homma Y, Kawakami Y (1998) Expression of epidermal growth factor and epidermal growth factor receptor immunoreactivity in the asthmatic human airway. Am J Respir Crit Care Med 157:1907–1912PubMedGoogle Scholar
  63. 63.
    Takeyama K, Fahy JV, Nadel JA (2001) Relationship of epidermal growth factor receptors to airway goblet cell production. Am J Respir Crit Care Med 163:511–516PubMedGoogle Scholar
  64. 64.
    Burgel PR, Nadel JA (2004) Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax 59:992–996PubMedCrossRefGoogle Scholar
  65. 65.
    Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7:505–516PubMedCrossRefGoogle Scholar
  66. 66.
    Calafat J, Janssen H, Stahle-Backdahl M, Zuurbier AE, Knol EF, Egesten A (1997) Human monocytes and neutrophils store transforming growth factor-alpha in a subpopulation of cytoplasmic granules. Blood 90:1255–1266PubMedGoogle Scholar
  67. 67.
    Burgel PR, Lazarus SC, Tam DC, Ueki IF, Atabai K, Birch M, Nadel JA (2001) Human eosinophils induce mucin production in airway epithelial cells via epidermal growth factor receptor activation. J Immunol 167:5948–5954PubMedGoogle Scholar
  68. 68.
    Wong DT, Weller PF, Galli SJ, Elovic A, Rand TH, Gallagher GT, Chiang T, Chou MY, Matossian K, McBride J (1990) Human eosinophils express transforming growth factor alpha. J Exp Med 172:673–681PubMedCrossRefGoogle Scholar
  69. 69.
    Okumura S, Sagara H, Fukuda T, Saito H, Okayama Y (2005) FcepsilonRI-mediated amphiregulin production by human mast cells increases mucin gene expression in epithelial cells. J Allergy Clin Immunol 115:272–279PubMedCrossRefGoogle Scholar
  70. 70.
    Rappolee DA, Mark D, Banda MJ, Werb Z (1988) Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science 241:708–712PubMedCrossRefGoogle Scholar
  71. 71.
    Polosa R, Prosperini G, Leir SH, Holgate ST, Lackie PM, Davies DE (1999) Expression of c-erbB receptors and ligands in human bronchial mucosa. Am J Respir Cell Mol Biol 20:914–923PubMedGoogle Scholar
  72. 72.
    Massague J, Pandiella A (1993) Membrane-anchored growth factors. Annu Rev Biochem 62:515–541PubMedCrossRefGoogle Scholar
  73. 73.
    Luttrell LM, Daaka Y, Lefkowitz RJ (1999) Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Curr Opin Cell Biol 11:177–183PubMedCrossRefGoogle Scholar
  74. 74.
    van Biesen T, Luttrell LM, Hawes BE, Lefkowitz RJ (1996) Mitogenic signaling via G protein-coupled receptors. Endocr Rev 17:698–714PubMedCrossRefGoogle Scholar
  75. 75.
    Gutkind JS (1998) The pathways connecting G protein-coupled receptors to the nucleus through divergent mitogen-activated protein kinase cascades. J Biol Chem 273:1839–1842PubMedCrossRefGoogle Scholar
  76. 76.
    Dhanasekaran N, Heasley LE, Johnson GL (1995) G protein-coupled receptor systems involved in cell growth and oncogenesis. Endocr Rev 16:259–270PubMedGoogle Scholar
  77. 77.
    Daub H, Weiss FU, Wallasch C, Ullrich A (1996) Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature 379:557–560PubMedCrossRefGoogle Scholar
  78. 78.
    Lazarowski ER, Boucher RC (2001) UTP as an extracellular signaling molecule. News Physiol Sci 16:1–5PubMedGoogle Scholar
  79. 79.
    Tsai W, Morielli AD, Peralta EG (1997) The m1 muscarinic acetylcholine receptor transactivates the EGF receptor to modulate ion channel activity. EMBO J 16:4597–4605PubMedCrossRefGoogle Scholar
  80. 80.
    Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C, Ullrich A (1999) EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402:884–888PubMedGoogle Scholar
  81. 81.
    Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN, Boyce RW, Nelson N, Kozlosky CJ, Wolfson MF, Rauch CT, Cerretti DP, Paxton RJ, March CJ, Black RA (1998) An essential role for ectodomain shedding in mammalian development. Science 282:1281–1284PubMedCrossRefGoogle Scholar
  82. 82.
    Kohri K, Ueki IF, Shim JJ, Burgel PR, Oh YM, Tam DC, Dao-Pick T, Nadel JA (2002) Pseudomonas aeruginosa induces MUC5AC production via epidermal growth factor receptor. Eur Respir J 20:1263–1270PubMedCrossRefGoogle Scholar
  83. 83.
    Shao MX, Ueki IF, Nadel JA (2003) Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci USA 100:11618–11623PubMedCrossRefGoogle Scholar
  84. 84.
    Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385:729–733PubMedCrossRefGoogle Scholar
  85. 85.
    Schlondorff J, Blobel CP (1999) Metalloprotease-disintegrins: modular proteins capable of promoting cell-cell interactions and triggering signals by protein-ectodomain shedding. J Cell Sci 112:3603–3617PubMedGoogle Scholar
  86. 86.
    Rahman I, MacNee W (2000) Oxidative stress and regulation of glutathione in lung inflammation. Eur Respir J 16:534–554PubMedCrossRefGoogle Scholar
  87. 87.
    Massion PP, Linden A, Inoue H, Mathy M, Grattan KM, Nadel JA (1996) Dimethyl sulfoxide decreases interleukin-8-mediated neutrophil recruitment in the airways. Am J Physiol 271:L838–843PubMedGoogle Scholar
  88. 88.
    Goldkorn T, Balaban N, Matsukuma K, Chea V, Gould R, Last J, Chan C, Chavez C (1998) EGF-Receptor phosphorylation and signaling are targeted by H2O2 redox stress. Am J Respir Cell Mol Biol 19:786–798PubMedGoogle Scholar
  89. 89.
    Gamou S, Shimizu N (1995) Hydrogen peroxide preferentially enhances the tyrosine phosphorylation of epidermal growth factor receptor. FEBS Lett 357:161–164PubMedCrossRefGoogle Scholar
  90. 90.
    Takeyama K, Dabbagh K, Jeong Shim J, Dao-Pick T, Ueki IF, Nadel JA (2000) Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: role of neutrophils. J Immunol 164:1546–1552PubMedGoogle Scholar
  91. 91.
    Shao MX, Nadel JA (2005) Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci USA 102:767–772PubMedCrossRefGoogle Scholar
  92. 92.
    De Deken X, Wang D, Many MC, Costagliola S, Libert F, Vassart G, Dumont JE, Miot F (2000) Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J Biol Chem 275:23227–23233PubMedCrossRefGoogle Scholar
  93. 93.
    Geiszt M, Witta J, Baffi J, Lekstrom K, Leto TL (2003) Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense. FASEB J 17:1502–1504PubMedGoogle Scholar
  94. 94.
    Kohri K, Ueki IF, Nadel JA (2002) Neutrophil elastase induces mucin production by ligand-dependent epidermal growth factor receptor activation. Am J Physiol Lung Cell Mol Physiol 283:L531–540PubMedGoogle Scholar
  95. 95.
    Kapp A, Zeck-Kapp G (1990) Activation of the oxidative metabolism in human polymorphonuclear neutrophilic granulocytes: the role of immuno-modulating cytokines. J Invest Dermatol 95:94S–99SPubMedCrossRefGoogle Scholar
  96. 96.
    Dusi S, Della Bianca V, Donini M, Nadalini KA, Rossi F (1996) Mechanisms of stimulation of the respiratory burst by TNF in nonadherent neutrophils: its independence of lipidic transmembrane signaling and dependence on protein tyrosine phosphorylation and cytoskeleton. J Immunol 157:4615–4623PubMedGoogle Scholar
  97. 97.
    Derevianko A, D'Amico R, Graeber T, Keeping H, Simms HH (1997) Endogenous PMN-derived reactive oxygen intermediates provide feedback regulation on respiratory burst signal transduction. J Leukoc Biol 62:268–276PubMedGoogle Scholar
  98. 98.
    Weissmann G, Smolen JE, Korchak HM (1980) Release of inflammatory mediators from stimulated neutrophils. N Engl J Med 303:27–34PubMedCrossRefGoogle Scholar
  99. 99.
    Weiss A, Karpf A, Luger E, Schmilowitz H, Dekel S, Shapira I (1998) Long-term antibiotic treatment in geriatric diabetic foot infection. J Med 29:365–373PubMedGoogle Scholar
  100. 100.
    Wanner A (1990) The role of mucus in chronic obstructive pulmonary disease. Chest 97:11S–15SPubMedGoogle Scholar
  101. 101.
    Fahy JV, Schuster A, Ueki I, Boushey HA, Nadel JA (1992) Mucus hypersecretion in bronchiectasis. The role of neutrophil proteases. Am Rev Respir Dis 146:1430–1433PubMedGoogle Scholar
  102. 102.
    Amishima M, Munakata M, Nasuhara Y, Sato A, Takahashi T, Homma Y, Kawakami Y (1998) Expression of epidermal growth factor and epidermal growth factor receptor immunoreactivity in the asthmatic human airway. Am J Respir Crit Care Med 157:1907–1912PubMedGoogle Scholar
  103. 103.
    Polosa R, Puddicombe SM, Krishna MT, Tuck AB, Howarth PH, Holgate ST, Davies DE (2002) Expression of c-erbB receptors and ligands in the bronchial epithelium of asthmatic subjects. J Allergy Clin Immunol 109:75–81PubMedCrossRefGoogle Scholar
  104. 104.
    Puddicombe SM, Polosa R, Richter A, Krishna MT, Howarth PH, Holgate ST, Davies DE (2000) Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J 14:1362–1374PubMedCrossRefGoogle Scholar
  105. 105.
    O'Donnell RA, Richter A, Ward J, Angco G, Mehta A, Rousseau K, Swallow DM, Holgate ST, Djukanovic R, Davies DE, Wilson SJ (2004) Expression of ErbB receptors and mucins in the airways of long term current smokers. Thorax 59:1032–1040PubMedCrossRefGoogle Scholar
  106. 106.
    de Boer WI, Hau CM, van Schadewijk A, Stolk J, van Krieken JH, Hiemstra PS (2006) Expression of epidermal growth factors and their receptors in the bronchial epithelium of subjects with chronic obstructive pulmonary disease. Am J Clin Pathol 125:184–192PubMedGoogle Scholar
  107. 107.
    Voynow JA, Fischer BM, Roberts BC, Proia AD (2005) Basal-like cells constitute the proliferating cell population in cystic fibrosis airways. Am J Respir Crit Care Med 172:1013–1018PubMedCrossRefGoogle Scholar
  108. 108.
    Hardie WD, Bejarano PA, Miller MA, Yankaskas JR, Ritter JH, Whitsett JA, Korfhagen TR (1999) Immunolocalization of transforming growth factor alpha and epidermal growth factor receptor in lungs of patients with cystic fibrosis. Pediatr Dev Pathol 2:415–423PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Nadel  Jay
    • 1
    • 2
  1. 1.Professor of Medicine, Physiology, and Radiology, Senior Staff Member, Cardiovascular Research Institute (CVRI), Director, NIH Multidisciplinary Research Training Program in Pulmonary Diseases (CVRI)University of CaliforniaSan FranciscoUSA
  2. 2.UCSF School of MedicineSan FranciscoUSA

Personalised recommendations