Current Allergy and Asthma Reports

, Volume 1, Issue 2, pp 108–115

Airway remodeling in the pathogenesis of asthma

  • Antonio M. Vignola
  • Rosalia Gagliardo
  • Antonella Siena
  • G. Chiappara
  • M. R. Bonsignore
  • Jean Bousquet
  • G. Bonsignore


Asthma is characterized by a chronic inflammatory process of the airways followed by healing, the end result of which is an altered structure referred to as airway remodeling. Although the mechanisms responsible for such structural alterations appear to be heterogeneous, it is likely that abnormal airway cell dedifferentiation, migration, and redifferentiation, together with changes in connective tissue deposition, contribute to the altered restitution of airway structure and function. This altered restitution is often seen as fibrosis and increased smooth muscle, mucus gland mass, and vessel area. As a consequence of these structural changes, the airway wall in asthma is usually characterized by increased thickness and markedly and permanently reduced airway caliber. These features may result in increased airflow resistance, particularly when there is bronchial contraction and bronchial hyperresponsiveness. The effect on airflow is compounded by increased mucus secretion and inflammatory exudate, which not only block the airway passages but also cause increased surface tension favoring airway closure.


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References and Recommended Reading

  1. 1.
    Cotran R, Kumar V, Robin S: Inflammation and repair. In Robbins Pathologic Basis of Disease, edn 4. Edited by Cotran R, Kumar V, Robbins SL. Philadelphia: Saunders; 1989:39–87.Google Scholar
  2. 2.
    Bousquet J, Jeffery PK, Busse WB, et al.: Asthma: from bronchoconstriction to airway remodelling. Am J Respir Crit Care Med 2000, 161:1720–1745. This review gives an overview of the biologic mechanisms underlying the pathogenesis of airway remodeling in asthma.PubMedGoogle Scholar
  3. 3.
    American Thoracic Society: Definitions and classifications of chronic bronchitis, asthma and emphysema. Am Rev Respir Dis 1962, 85:762–768.Google Scholar
  4. 4.
    Bousquet J, Chanez P, Lacoste JY, et al.: Asthma: a disease remodeling the airways. Allergy 1992, 47:3–11.PubMedCrossRefGoogle Scholar
  5. 5.
    Chung KF, Barnes PJ: Cytokines in asthma. Thorax 1999, 54:825–857.PubMedCrossRefGoogle Scholar
  6. 6.
    Meerschaert J, Kelly EA, Mosher DF, et al.: Segmental antigen challenge increases fibronectin in bronchoalveolar lavage fluid. Am J Respir Crit Care Med 1999, 159:619–625.PubMedGoogle Scholar
  7. 7.
    Stetler-Stevenson WG: Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention. J Clin Invest 1999, 103:1237–1241.PubMedGoogle Scholar
  8. 8.
    Holgate ST, Davies DE, Lackie PM, et al.: Epithelialmesenchymal interactions in the pathogenesis of asthma. J Allergy Clin Immunol 2000, 105:193–204. In this paper it is suggested that the extent of epithelial damage in asthma may be the result of impaired EGF receptor-mediated repair. In view of the close spatial relationship between the damaged epithelium and the underlying myofibroblasts, it is proposed that impaired epithelial repair cooperates with the TH2 environment to shift the set point for communication within the trophic unit. This leads to myofibroblast activation, excessive matrix deposition, and production of mediators that propagate and amplify the remodeling responses throughout the airway wall.PubMedCrossRefGoogle Scholar
  9. 9.
    Sun G, Stacey MA, Bellini A, et al.: Endothelin-1 induces bronchial myofibroblast differentiation. Peptides 1997, 18:1449–1451.PubMedCrossRefGoogle Scholar
  10. 10.
    Leslie KO, Mitchell J, Low R: Lung myofibroblasts. Cell Motil Cytoskeleton 1992, 22:92–98.PubMedCrossRefGoogle Scholar
  11. 11.
    Brewster CE, Howarth PH, Djukanovic R, et al.: Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 1990, 3:507–511.PubMedGoogle Scholar
  12. 12.
    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
  13. 13.
    Ohno I, Lea RG, Flanders KC, et al.: Eosinophils in chronically inflamed human upper airway tissues express transforming growth factor beta 1 gene (TGF beta 1). J Clin Invest 1992, 89:1662–1668.PubMedCrossRefGoogle Scholar
  14. 14.
    Lungarella G, Menegazzi R, Gardi C, et al.: Identification of elastase in human eosinophils: immunolocalization, isolation, and partial characterization. Arch Biochem Biophys 1992, 292:128–135.PubMedCrossRefGoogle Scholar
  15. 15.
    Vignola A, Chanez P, Chiappara G, et al.: Release of transforming growth factor-b and fibronectin by alveolar macrophages in airway diseases. Clin Exp Immunol 1996, 106:114–119.PubMedCrossRefGoogle Scholar
  16. 16.
    Moreno RH, Hogg JC, Pare PD: Mechanics of airway narrowing. Am Rev Respir Dis 1986, 133:1171–1180.PubMedGoogle Scholar
  17. 17.
    Roche WR, Beasley R, Williams JH, Holgate ST: Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1989, 1:520–524.PubMedCrossRefGoogle Scholar
  18. 18.
    Jeffery PK, Wardlaw AJ, Nelson FC, et al.: Bronchial biopsies in asthma: an ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 1989, 140:1745–1753.PubMedGoogle Scholar
  19. 19.
    Chetta A, Foresi A, Del-Donno M, et al.: Airways remodeling is a distinctive feature of asthma and is related to severity of disease. Chest 1997, 111:852–857.PubMedGoogle Scholar
  20. 20.
    Niimi A, Matsumoto H, Masayoshi M, et al.: Airway remodelling in cough-variant asthma. Lancet 2000, 356:564–565.PubMedCrossRefGoogle Scholar
  21. 21.
    Wenzel SE, Schwartz LB, Langmack EL, et al.: Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999, 160:1001–1008.PubMedGoogle Scholar
  22. 22.
    Bousquet J, Lacoste J, Chanez P, et al.: Bronchial elastic fibers in normal subjects and asthmatic patients. Am J Respir Crit Care Med 1996, 153:1648–1653.PubMedGoogle Scholar
  23. 23.
    Mauad T, Xavier AC, Saldiva PH, Dolhnikoff M: Elastosis and fragmentation of fibers of the elastic system in fatal asthma. Am J Respir Crit Care Med 1999, 160:968–975.PubMedGoogle Scholar
  24. 24.
    Carroll NG, Perry S, Karkhanis A, et al.: The airway longitudinal elastic fiber network and mucosal folding in patients with asthma. Am J Respir Crit Care Med 2000, 161:244–248. The authors show that collagen and myofibroblasts are increased in longitudinal bundles of airways of fatal and nonfatal asthma cases compared with nonasthma control cases. It is suggested that increased size and altered composition of longitudinal bundles in asthma may influence airway function.PubMedGoogle Scholar
  25. 25.
    Bousquet J, Chanez P, Lacoste JY, et al.: Indirect evidence of bronchial inflammation assessed by titration of inflammatory mediators in BAL fluid of patients with asthma. J Allergy Clin Immunol 1991, 88:649–660.PubMedCrossRefGoogle Scholar
  26. 26.
    Laitinen A, Altraja A, Kampe M, et al.: Tenascin is increased in airway basement membrane of asthmatics and decreased by an inhaled steroid. Am J Respir Crit Care Med 1997, 156:951–958.PubMedGoogle Scholar
  27. 27.
    Vignola AM, Chanez P, Chiappara G, et al.: Transforming growth factor-β expression in mucosal biopsies in asthma and chronic bronchitis. Am J Respir Crit Care Med 1997, 156:591–599.PubMedGoogle Scholar
  28. 28.
    Ohno K, Ammann P, Fasciati R, Maier P: Transforming growth factor beta 1 preferentially induces apoptotic cell death in rat hepatocytes cultured under pericentral-equivalent conditions. Toxicol Appl Pharmacol 1995, 132:227–236.PubMedCrossRefGoogle Scholar
  29. 29.
    Chanez P, Vignola M, Steinger R, et al.: Platelet-derived growth factor in asthma. Allergy 1995, 50:878–883.PubMedCrossRefGoogle Scholar
  30. 30.
    Mautino G, Capony F, Bousquet J, Vignola AM: Balance in asthma between matrix metalloproteinases and their inhibitors [editorial]. J Allergy Clin Immunol 1999, 104:530–533.PubMedCrossRefGoogle Scholar
  31. 31.
    Mautino G, Henriquet C, Oliver N, et al.: Elevated levels of tissue inhibitor of metalloproteinase-1 in bronchoalveolar lavage of asthmatic patients. Lab Invest 1999, 79:39–47.PubMedGoogle Scholar
  32. 32.
    Hoshino M, Nakamura Y, Sim J, et al.: Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation. J Allergy Clin Immunol 1998, 102:783–788.PubMedCrossRefGoogle Scholar
  33. 33.
    Vignola AM, Riccobono L, Mirabella A, et al.: Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am J Respir Crit Care Med 1998, 158:1945–1950. This study concentrates on the potential role played by MMPs and their inhibitors (TIMPs) in airway remodeling in asthma. The increased TIMP-1 over MMP-9 ratio supports the concept that in asthma there is a trend towards fibrosis, which may be due to an inhibition of collagen degradation.PubMedGoogle Scholar
  34. 34.
    Li X, Wilson JW: Increased vascularity of the bronchial mucosa in mild asthma. Am J Respir Crit Care Med 1997, 156:229–233.PubMedGoogle Scholar
  35. 35.
    Carroll N, Elliot J, Morton A, James A: The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993, 147:405–410.PubMedGoogle Scholar
  36. 36.
    Sobonya RE: Quantitative structural alterations in long-standing allergic asthma. Am Rev Respir Dis 1984, 130:289–292.PubMedGoogle Scholar
  37. 37.
    Salmon M, Walsh DA, Koto H, et al.: Repeated allergen exposure of sensitized Brown-Norway rats induces airway cell DNA synthesis and remodelling. Eur Respir J 1999, 14:633–641.PubMedCrossRefGoogle Scholar
  38. 38.
    Dunnill M, Massarella G, Anderson J: Comparaison 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
  39. 39.
    Woolcock AJ, Salome CM, Yan K: The shape of the dose-response curve to histamine in asthmatic and normal subjects. Am Rev Respir Dis 1984, 130:71–75.PubMedGoogle Scholar
  40. 40.
    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
  41. 41.
    Brown RH, Zerhouni EA, Mitzner W: Airway edema potentiates airway reactivity. J Appl Physiol 1995, 79:1242–1248.PubMedGoogle Scholar
  42. 42.
    Kips JC, Pauwels RA: Airway wall remodelling: does it occur and what does it mean? Clin Exp Allergy 1999, 29:1457–1466.PubMedCrossRefGoogle Scholar
  43. 43.
    Backman KS, Greenberger PA, Patterson R: Airways obstruction in patients with long-term asthma consistent with ‘irreversible asthma’. Chest 1997, 112:1234–1240.PubMedGoogle Scholar
  44. 44.
    Lange P, Parner J, Vestbo J, et al.: A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998, 339:1194–1200.PubMedCrossRefGoogle Scholar
  45. 45.
    Paganin F, Seneterre E, Chanez P, et al.: Computed tomography of the lungs in asthma: influence of disease severity and etiology. Am J Respir Crit Care Med 1996, 153:110–114.PubMedGoogle Scholar
  46. 46.
    Boulet LP, Turcotte H, Hudon C, et al.: Clinical, physiological and radiological features of asthma with incomplete reversibility of airflow obstruction compared with those of COPD. Can Respir J 1998, 5:270–277.PubMedGoogle Scholar
  47. 47.
    Lundgren R, Soderberg M, Horstedt P, Stenling R: Morphological studies of bronchial mucosal biopsies from asthmatics before and after ten years of treatment with inhaled steroids. Eur Respir J 1988, 1:883–889.PubMedGoogle Scholar
  48. 48.
    Trigg CJ, Manolitsas ND, Wang J, et al.: Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma. Am J Respir Crit Care Med 1994, 150:17–22.PubMedGoogle Scholar
  49. 49.
    Sont JK, Willems LN, Bel EH, et al.: Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment: the AMPUL Study Group. Am J Respir Crit Care Med 1999, 159:1043–1051. This study shows that reducing airway hyperresponsiveness in conjunction with optimizing symptoms and lung function leads to more effective control of asthma while alleviating chronic airway inflammation. This implies a role for the monitoring of airway hyperresponsiveness or other surrogate markers of inflammation in the long-term management of asthma.PubMedGoogle Scholar
  50. 50.
    Orsida BE, Li X, Hickey B, et al.: Vascularity in asthmatic airways: relation to inhaled steroid dose. Thorax 1999, 54:289–295.PubMedCrossRefGoogle Scholar
  51. 51.
    van-Essen-Zandvliet EE, Hughes MD, Waalkens HJ, et al.: Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and symptoms in children with asthma: the Dutch Chronic Non-specific Lung Disease Study Group. Am Rev Respir Dis 1992, 146:547–554.PubMedGoogle Scholar
  52. 52.
    Vanacker NJ, Palmans E, Kips JC, Pauwels RA: The effect of pretreatment with fluticasone on allergen induced airway changes in a rat model. Am J Respir Crit Care Med 1999, 159:A115.Google Scholar
  53. 53.
    The Childhood Asthma Management Program Research Group: Long-term effects of budesonide or nedocromil in children with asthma: the Childhood Asthma Management Program Research Group. N Engl J Med 2000, 12:1054–1063. This prospective study was conducted in asthmatic children to examine the effect of long-term treatment with inhaled budesonide on adult height and lung growth, as assessed by the change in FEV1 after bronchodilator administration. The use of budesonide was associated with improvement in FEV1 after bronchodilator administration within 2 months. However, this improvement gradually diminished by the end of the treatment period, at which point the change was not significantly different compared with that seen in placebo-treated patients. Such a lack of long-term improvement in FEV1 after treatment with corticosteroids raises the question of whether steroids can reverse or prevent the development of structural changes of the airways.CrossRefGoogle Scholar

Copyright information

© Current Science Inc. 2001

Authors and Affiliations

  • Antonio M. Vignola
    • 1
    • 2
  • Rosalia Gagliardo
    • 1
  • Antonella Siena
    • 1
  • G. Chiappara
    • 1
  • M. R. Bonsignore
    • 1
  • Jean Bousquet
    • 3
  • G. Bonsignore
    • 1
  1. 1.Istituto di Fisiopatologia Respiratoria, CNRPalermoItaly
  2. 2.Clinica Malattie RespiratorieUniversity of PalermoPalermoItaly
  3. 3.Clinique des Maladies Respiratoires and INSERM U454, CHUMontpellierFrance

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