Current Allergy and Asthma Reports

, Volume 8, Issue 6, pp 540–547

Structural aspects of airway remodeling in asthma



Airway remodeling in asthma is a complex process that involves structural changes in virtually all tissues of the airway wall. The histologic changes to the airways consist of epithelial proliferation and goblet cell differentiation, subepithelial fibrosis, airway smooth muscle (ASM) growth, angiogenesis, matrix protein deposition, gland hyperplasia and hypertrophy, and nerve proliferation. Cytokines, chemokines, and growth factors from inflammatory cells and structural cells contribute to remodeling. There are complex interactions among the various signaling pathways involving matrix metalloproteinases that are required for growth factor release. The physiologic consequences of remodeling are airway hyperresponsiveness from ASM growth and mucus hypersecretion from gland and goblet cell hyperplasia. Airway stiffening is a probable contributor to airway hyperresponsiveness through attenuation of the transmission of potently bronchodilating cyclical stress to the ASM during breathing. The epidermal growth factor receptor’s role in remodeling and its interaction with other potential causes of remodeling are discussed.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Pearce N, Pekkanen J, Beasley R: How much asthma is really attributable to atopy? Thorax 1999, 54:268–272.PubMedGoogle Scholar
  2. 2.
    Ramos-Barbon D, Presley JF, Hamid QA, et al.: Antigen-specific CD4+ T cells drive airway smooth muscle remodeling in experimental asthma. J Clin Invest 2005, 115:1580–1589.PubMedCrossRefGoogle Scholar
  3. 3.
    Allahverdian S, Harada N, Singhera GK, et al.: Secretion of IL-13 by airway epithelial cells enhances epithelial repair via HB-EGF. Am J Respir Cell Mol Biol 2008, 38:153–160.PubMedCrossRefGoogle Scholar
  4. 4.
    Casalino-Matsuda SM, Monzon ME, Forteza RM: Epidermal growth factor receptor activation by epidermal growth factor mediates oxidant-induced goblet cell metaplasia in human airway epithelium. Am J Respir Cell Mol Biol 2006, 34:581–591.PubMedCrossRefGoogle Scholar
  5. 5.
    Vermeer PD, Harson R, Einwalter LA, et al.: Interleukin-9 induces goblet cell hyperplasia during repair of human airway epithelia. Am J Respir Cell Mol Biol 2003, 28:286–295.PubMedCrossRefGoogle Scholar
  6. 6.
    Xiang YY, Wang S, Liu M, et al.: A GABAergic system in airway epithelium is essential for mucus overproduction in asthma. Nat Med 2007, 13:862–867.PubMedCrossRefGoogle Scholar
  7. 7.
    Shao MX, Nadel JA: 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 2005, 175:4009–4016.PubMedGoogle Scholar
  8. 8.
    Amishima M, Munakata M, Nasuhara Y, et al.: Expression of epidermal growth factor and epidermal growth factor receptor immunoreactivity in the asthmatic human airway. Am J Respir Crit Care Med 1998, 157:1907–1912.PubMedGoogle Scholar
  9. 9.
    Nadel JA: Innate immune mucin production via epithelial cell surface signaling: relationship to allergic disease. Curr Opin Allergy Clin Immunol 2007, 7:57–62.PubMedCrossRefGoogle Scholar
  10. 10.
    Koff JL, Shao MX, Ueki IF, et al.: Multiple TLRs activate EGFR via a signaling cascade to produce innate immune responses in airway epithelium. Am J Physiol Lung Cell Mol Physiol 2008, 294:L1068–L1075.PubMedCrossRefGoogle Scholar
  11. 11.
    Koff JL, Shao MX, Kim S, et al.: Pseudomonas lipopolysaccharide accelerates wound repair via activation of a novel epithelial cell signaling cascade. J Immunol 2006, 177:8693–8700.PubMedGoogle Scholar
  12. 12.
    Chokki M, Mitsuhashi H, Kamimura T: Metalloproteasedependent amphiregulin release mediates tumor necrosis factor-alpha-induced IL-8 secretion in the human airway epithelial cell line NCI-H292. Life Sci 2006, 78:3051–3057.PubMedCrossRefGoogle Scholar
  13. 13.
    Poynter ME, Cloots R, van Woerkom T, et al.: NF-kappa B activation in airways modulates allergic inflammation but not hyperresponsiveness. J Immunol 2004, 173:7003–7009.PubMedGoogle Scholar
  14. 14.
    Cohn L: Mucus in chronic airway diseases: sorting out the sticky details. J Clin Invest 2006, 116:306–308.PubMedCrossRefGoogle Scholar
  15. 15.
    Lordan JL, Bucchieri F, Richter A, et al.: Cooperative effects of Th2 cytokines and allergen on normal and asthmatic bronchial epithelial cells. J Immunol 2002, 169:407–414.PubMedGoogle Scholar
  16. 16.
    Ravasi S, Citro S, Viviani B, et al.: CysLT1 receptor-induced human airway smooth muscle cells proliferation requires ROS generation, EGF receptor transactivation and ERK1/2 phosphorylation. Respir Res 2006, 7:42.PubMedCrossRefGoogle Scholar
  17. 17.
    Vargaftig BB, Singer M: Leukotrienes mediate part of ovainduced lung effects in mice via EGFR. Am J Physiol Lung Cell Mol Physiol 2003, 285:L808–L818.PubMedGoogle Scholar
  18. 18.
    Kelly MM, Leigh R, Bonniaud P, et al.: Epithelial expression of profibrotic mediators in a model of allergen-induced airway remodeling. Am J Respir Cell Mol Biol 2005, 32:99–107.PubMedCrossRefGoogle Scholar
  19. 19.
    Ebina M, Takahashi T, Chiba T, et al.: Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma. A 3-D morphometric study. Am Rev Respir Dis 1993, 148:720–726.PubMedGoogle Scholar
  20. 20.
    Woodruff PG, Dolganov GM, Ferrando RE, et al.: Hyperplasia of smooth muscle in mild to moderate asthma without changes in cell size or gene expression. Am J Respir Crit Care Med 2004, 169:1001–1006.PubMedCrossRefGoogle Scholar
  21. 21.
    Dunnill MS, Masarrella GR, Anderson JA: A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis and in emphysema. Thorax 1969, 24:176–179.PubMedCrossRefGoogle Scholar
  22. 22.
    Heard B, Hossain S: Hyperplasia of bronchial muscle in asthma. J Pathol 1973, 110:319–331.CrossRefGoogle Scholar
  23. 23.
    Pepe C, Foley S, Shannon J, et al.: Differences in airway remodeling between subjects with severe and moderate asthma. J Allergy Clin Immunol 2005, 116:544–549.PubMedCrossRefGoogle Scholar
  24. 24.
    Panettieri RA, Murray RK, Bilgen G, et al.: Repeated allergen inhalations induce DNA synthesis in airway smooth muscle and epithelial cells in vivo. Chest 1995, 107:S94–S95.CrossRefGoogle Scholar
  25. 25.
    Ward JE, Harris T, Bamford T, et al.: Proliferation is not increased in airway myofibroblasts isolated from asthmatics. Eur Respir J 2008 Mar 19 (Epub ahead of print).Google Scholar
  26. 26.
    Schmidt M, Sun G, Stacey MA, et al.: Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 2003, 171:380–389.PubMedGoogle Scholar
  27. 27.
    Johnson PR, Roth M, Tamm M, et al.: Airway smooth muscle cell proliferation is increased in asthma. Am J Respir Crit Care Med 2001, 164:474–477.PubMedGoogle Scholar
  28. 28.
    Carroll N, Elliot J, Morton A, et al.: The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993, 147:405–410.PubMedGoogle Scholar
  29. 29.
    Moir LM, Leung SY, Eynott PR, et al.: Repeated allergen inhalation induces phenotypic modulation of airway smooth muscle in small bronchioles of sensitized rats. Am J Physiol Lung Cell Mol Physiol 2003, 284:L148–L159.PubMedGoogle Scholar
  30. 30.
    Wang CG, Du T, Xu LJ, et al.: Role of leukotriene D4 in allergen-induced increases in airway smooth muscle in the rat. Am Rev Respir Dis 1993, 148:413–417.PubMedGoogle Scholar
  31. 31.
    Salmon M, Liu YC, Mak JC, et al.: Contribution of upregulated airway endothelin-1 expression to airway smooth muscle and epithelial cell DNA synthesis after repeated allergen exposure of sensitized Brown-Norway rats. Am J Respir Cell Mol Biol 2000, 23:618–625.PubMedGoogle Scholar
  32. 32.
    Henderson WR Jr, Chiang GK, Tien YT, et al.: Reversal of allergen-induced airway remodeling by CysLT1 receptor blockade. Am J Respir Crit Care Med 2006, 173:718–728.PubMedCrossRefGoogle Scholar
  33. 33.
    Leigh R, Ellis R, Wattlie JN, et al.: Type 2 cytokines in the pathogenesis of sustained airway dysfunction and airway remodeling in mice. Am J Respir Crit Care Med 2004, 169:860–867.PubMedCrossRefGoogle Scholar
  34. 34.
    Espinosa K, Bosse Y, Stankova J, et al.: CysLT1 receptor upregulation by TGF-beta and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4. J Allergy Clin Immunol 2003, 111:1032–1040.PubMedCrossRefGoogle Scholar
  35. 35.
    Bosse Y, Thompson C, Audette K, et al.: Interleukin-4 and interleukin-13 enhance human bronchial smooth muscle cell proliferation. Int Arch Allergy Immunol 2008, 146:138–148.PubMedCrossRefGoogle Scholar
  36. 36.
    Hawker KM, Johnson PR, Hughes JM, et al.: Interleukin-4 inhibits mitogen-induced proliferation of human airway smooth muscle cells in culture. Am J Physiol 1998, 275:L469–L477.PubMedGoogle Scholar
  37. 37.
    Finotto S, Hausding M, Doganci A, et al.: Asthmatic changes in mice lacking T-bet are mediated by IL-13. Int Immunol 2005, 17:993–1007.PubMedCrossRefGoogle Scholar
  38. 38.
    Panettieri RA, Tan EM, Ciocca V, et al.: Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction in vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists. Am J Respir Cell Mol Biol 1998, 19:453–461.PubMedGoogle Scholar
  39. 39.
    Holgate ST, Holloway J, Wilson S, et al.: Epithelial-mesenchymal communication in the pathogenesis of chronic asthma. Proc Am Thorac Soc 2004, 1:93–98.PubMedCrossRefGoogle Scholar
  40. 40.
    Hashimoto S, Gon Y, Takeshita I, et al.: Transforming growth factor-beta1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway. Am J Respir Crit Care Med 2001, 163:152–157.PubMedGoogle Scholar
  41. 41.
    Gizycki MJ, Adelroth E, Rogers AV, et al.: Myofibroblast involvement in the allergen-induced late response in mild atopic asthma. Am J Respir Cell Mol Biol 1997, 16:664–673.PubMedGoogle Scholar
  42. 42.
    Palmans E, Kips JC, Pauwels RA: Prolonged allergen exposure induces structural airway changes in sensitized rats. Am J Respir Crit Care Med 2000, 161:627–635.PubMedGoogle Scholar
  43. 43.
    Pini L, Torregiani C, Martin JG, et al.: Airway remodeling in allergen-challenged Brown Norway rats: distribution of proteoglycans. Am J Physiol Lung Cell Mol Physiol 2006, 290:L1052–L1058.PubMedCrossRefGoogle Scholar
  44. 44.
    Johnson PR, Burgess JK, Underwood PA, et al.: Extracellular matrix proteins modulate asthmatic airway smooth muscle cell proliferation via an autocrine mechanism. J Allergy Clin Immunol 2004, 113:690–696.PubMedCrossRefGoogle Scholar
  45. 45.
    D’Antoni ML, Torregiani C, Ferraro P, et al.: Effects of decorin and biglycan on human airway smooth muscle cell proliferation and apoptosis. Am J Physiol Lung Cell Mol Physiol 2008, 294:L764–L771.PubMedCrossRefGoogle Scholar
  46. 46.
    Postlethwaite AE, Keski-Oja J, Moses HL, et al.: Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. J Exp Med 1987, 165:251–256.PubMedCrossRefGoogle Scholar
  47. 47.
    Batra V, Musani AI, Hastie AT, et al.: Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)-beta1, TGF-beta2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on alpha-smooth muscle actin and collagen III synthesis by primary human lung fibroblasts. Clin Exp Allergy 2004, 34:437–444.PubMedCrossRefGoogle Scholar
  48. 48.
    Lewis CC, Chu HW, Westcott JY, et al.: Airway fibroblasts exhibit a synthetic phenotype in severe asthma. J Allergy Clin Immunol 2005, 115:534–540.PubMedCrossRefGoogle Scholar
  49. 49.
    Chen C, Huang X, Sheppard D: ADAM33 is not essential for growth and development and does not modulate allergic asthma in mice. Mol Cell Biol 2006, 26:6950–6956.PubMedCrossRefGoogle Scholar
  50. 50.
    Brightling CE, Bradding P, Symon FA, et al.: Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002, 346:1699–1705.PubMedCrossRefGoogle Scholar
  51. 51.
    Begueret H, Berger P, Vernejoux JM, et al.: Inflammation of bronchial smooth muscle in allergic asthma. Thorax 2007, 62:8–15.PubMedCrossRefGoogle Scholar
  52. 52.
    Okayama Y, Ra C, Saito H: Role of mast cells in airway remodeling. Curr Opin Immunol 2007, 19:687–693.PubMedCrossRefGoogle Scholar
  53. 53.
    Sutcliffe A, Kaur D, Page S, et al.: Mast cell migration to Th2 stimulated airway smooth muscle from asthmatics. Thorax 2006, 61:657–662.PubMedCrossRefGoogle Scholar
  54. 54.
    Brightling CE, Ammit AJ, Kaur D, et al.: The CXCL10/ CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle. Am J Respir Crit Care Med 2005, 171:1103–1108.PubMedCrossRefGoogle Scholar
  55. 55.
    Kaur D, Saunders R, Berger P, et al.: Airway smooth muscle and mast cell-derived CC chemokine ligand 19 mediate airway smooth muscle migration in asthma. Am J Respir Crit Care Med 2006, 174:1179–1188.PubMedCrossRefGoogle Scholar
  56. 56.
    Zaiss DM, Yang L, Shah PR, et al.: Amphiregulin, a Th2 cytokine enhancing resistance to nematodes. Science 2006, 314:1746.PubMedCrossRefGoogle Scholar
  57. 57.
    Kumar RK, Herbert C, Foster PS: Expression of growth factors by airway epithelial cells in a model of chronic asthma: regulation and relationship to subepithelial fibrosis. Clin Exp Allergy 2004, 34:567–575.PubMedCrossRefGoogle Scholar
  58. 58.
    Machida I, Matsuse H, Kondo Y, et al.: Cysteinyl leukotrienes regulate dendritic cell functions in a murine model of asthma. J Immunol 2004, 172:1833–1838.PubMedGoogle Scholar
  59. 59.
    Gunst SJ, Stropp JQ: Pressure-volume and length-stress relationships in canine bronchi in vitro. J Appl Physiol 1995, 64:2522–2531.Google Scholar
  60. 60.
    Fredberg JJ, Inouye D, Miller B, et al.: Airway smooth muscle, tidal stretches, and dynamically determined contractile states. Am J Respir Crit Care Med 1997, 156:1752–1759.PubMedGoogle Scholar
  61. 61.
    Lambert RK, Wiggs BR, Kuwano K, et al.: Functional significance of increased airway smooth muscle in asthma and COPD. J Appl Physiol 1993, 74:2771–2781.PubMedCrossRefGoogle Scholar
  62. 62.
    Niimi A, Matsumoto H, Takemura M, et al.: Relationship of airway wall thickness to airway sensitivity and airway reactivity in asthma. Am J Respir Crit Care Med 2003, 168:983–988.PubMedCrossRefGoogle Scholar
  63. 63.
    Pare PD: Airway hyperresponsiveness in asthma: geometry is not everything! Am J Respir Crit Care Med 2003, 168:913–914.PubMedCrossRefGoogle Scholar
  64. 64.
    Hirst SJ, Twort CH, Lee TH: Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype. Am J Respir Cell Mol Biol 2000, 23:335–344.PubMedGoogle Scholar
  65. 65.
    Bonacci JV, Harris T, Stewart AG: Impact of extracellular matrix and strain on proliferation of bovine airway smooth muscle. Clin Exp Pharmacol Physiol 2003, 30:324–328.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Meakins Christie LaboratoriesMcGill UniversityMontrealCanada

Personalised recommendations