Airway Remodeling and Repair

  • Peter M. Hockey
  • Ratko Djukanović
  • William R. Roche
  • Steven T. Holgate


It is now universally accepted that asthma is a disease process revolving around inflammation and its effects on airway pathophysiology. The inflammatory features of asthma are characterized by immunohistological and cytokine profiles that appear to be specific for asthma and, importantly, are not demonstrable in the nonatopic, nonasthmatic, normal individual. They have been shown to include edema, hyperplasia of mucus-secreting cells, hypertrophy of smooth muscle, collagen deposition beneath the epithelial basement membrane, intraluminal cellular and mucus debris, cellular infiltration of the epithelium, and sloughing of the epithelial cell layer with subsequent denudation of the normal air-tissue interface. These changes have been shown to be present to a varying degree in patients with mild, asymptomatic disease right through to those dying in status asthmaticus. Although considerable attention has focused on the documentation of morphological abnormalities, especially by means of bronchial biopsy studies, to date comparatively little attention has been paid to the healing process. As with inflammatory processes in other tissues, chronic insult to the airways is likely to lead to a cycle of inflammation and repair, although the factors that determine the balance between the two remain largely unknown (1).


Mast Cell Allergy Clin Immunol Respir Crit Bronchial Epithelial Cell Airway Epithelial Cell 
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.
    Holgate ST. The inflammation-repair cycle in asthma. Eur Respir Rev, in press.Google Scholar
  2. 2.
    Burrows B, Lebowitz MD, Barbee RA, Cline MG (1991) Findings before diagnoses of asthma among the elderly in a longitudinal study of a general population sample. J Allergy Clin Immunol 88: 870–877.PubMedCrossRefGoogle Scholar
  3. 3.
    Stewart AG, Tomlinson PR, Wilson J (1993) Airway wall remodelling in asthma: a novel target for the development of anti-asthma drugs. Trends Pharmacol Sci 14: 275–279.PubMedCrossRefGoogle Scholar
  4. 4.
    Paganin F, Seneterre E, Chanez P, Daures JP, Bruel JM, Michel FB, Bousquet J (1996) Computed tomography of the lungs in asthma: influence of disease severity and etiology. Am J Respir Crit Care Med 153: 110–114.PubMedGoogle Scholar
  5. 5.
    Lynch DA, Newell JD, Tschomper BA, Cink TM, Newman LS, Bethel R (1994) Uncomplicated asthma in adults: comparison of CT appearance of the lungs in asthmatic and healthy subjects. Radiology 188: 829–833.Google Scholar
  6. 6.
    Raeburn D, Webber SE (1994) Proinflammatory potential of the airway epithelium in bronchial asthma. Eur Respir J 7: 2226–2233.PubMedCrossRefGoogle Scholar
  7. 7.
    Montefort S, Roberts JA, Beasley R, Holgate ST, Roche W (1992) The site of disruption of the bronchial epithelium in asthmatic and non-asthmatic subjects. Thorax 47: 499–503.PubMedCrossRefGoogle Scholar
  8. 8.
    Montefort S, Roche WR, Holgate ST (1993) Bronchial epithelial shedding in asthmatics and non-asthmatics. Respir Med 87: S9 — S11.CrossRefGoogle Scholar
  9. 9.
    Bradding P, Redington AE, Djukanovic R, Conrad DJ, Holgate ST (1995) 15–1 ipoxygenase immunoreactivity in normal and asthmatic airways. Am J Respir Crit Care Med 151: 1201–1204.Google Scholar
  10. 10.
    Shannon VR, Chanez P, Bousquet J, Holtzman MJ (1993) Histochemical evidence for induction of arachidonate 15-lipoxygenase in airway disease. Am Rev Respir Dis 147: 1024–1028.PubMedGoogle Scholar
  11. 11.
    Springall DR, Meng Q-H, Redington AE, Howarth PH, Polak JM (1995) Inflammatory genes in asthmatic airway epithelium: suppression by corticosteroids. Eur Respir J 8: 445 (abstract).Google Scholar
  12. 12.
    Springall DR, Howarth PH, Counihan H, Djukanovic R, Holgate ST, Polak JM (1991) Endothelin immunoreactivity of airway epithelium in asthmatic patients. Lancet 337: 697–701.PubMedCrossRefGoogle Scholar
  13. 13.
    Albelda SM (1991) Endothelial and epithelial cell adhesion molecules. Am J Respir Cell Mol Biol 4: 195–203.PubMedGoogle Scholar
  14. 14.
    Bousquet J, Vignola AM, Chanez P, Campbell AM, Bonsignore G, Michel F-B (1995) Airways remodelling in asthma: no doubt, no more? Int Arch Allergy Immunol 107: 211–214.PubMedCrossRefGoogle Scholar
  15. 15.
    Marini M, Vittori E, Hollemborg J, Mattoli S (1992) Expression of the potent inflammatory cytokines, granulocyte colony-stimulating factor and interleukin-6 and interleukin-8, in bronchial epithelial cells of patients with asthma. J Allergy Clin Immunol 89: 1001–1009.PubMedCrossRefGoogle Scholar
  16. 16.
    Zhang S, Mohammed Q, Burbidge A, Morland CM, Roche WR (1996) Cell cultures from bronchial subepithelial myofibroblasts enhance eosinophil survival in vitro. Eur Respir J 9: 1839–1846.PubMedCrossRefGoogle Scholar
  17. 17.
    Pons F, Boichot E, Lagente V, Touvay C, Mencia-Huerta JM, Braquet P (1991) Role of endothelia in pulmonary function. Pulmon Pharmacol 5: 213–219.CrossRefGoogle Scholar
  18. 18.
    Raghow R (1994) The role of extracellular matrix in post inflammatory wound healing and fibrosis. FASEB J 8: 823–831.PubMedGoogle Scholar
  19. 19.
    Holgate ST, Wilson JR, Howarth PH (1992) New insights into airway inflammation by endobronchial biopsy. Am Rev Respir Dis 145: S2 - S6.PubMedGoogle Scholar
  20. 20.
    Roche WR, Beasley R, Williams JH, Holgate ST (1989) Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1: 5520–5524.Google Scholar
  21. 21.
    Laitinen LA, Laitinen A (1995) Inhaled corticosteroid treatment and extracellular matrix in the airways in asthma. Int Arch Allergy Immunol 107: 215–216.PubMedCrossRefGoogle Scholar
  22. 22.
    Laitinen A, Altraja A, Linden M, Stallenheim G, Venge P, Hakansson L, Virtanen I, Laitinen LA (1994) Treatment with inhaled budesonide and tenascin expression in bronchial mucosa of allergic asthmatics. Am J Respir Crit Care Med 149: A942.Google Scholar
  23. 23.
    Trigg CJ, Manolitsas ND, Wang J, Calderon MA, McAulay A, Jordan SE, Herdman MJ, Jhalli N, Duddle JM, Hamilton SA, Devalia JL, Davies RJ (1994) Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma Am J Respir Crit Care Med 150: 17–22.Google Scholar
  24. 24.
    Zhang S, Howarth PH, Roche WR (1996) Cytokine production by bronchial myofibroblasts. J Pathol 180: 95–101.PubMedCrossRefGoogle Scholar
  25. 25.
    Brewster CEP, Howarth PH, Djukanovic R, Wilson J, Holgate ST, Roche WR (1990) Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 3: 507–511.PubMedGoogle Scholar
  26. 26.
    Thomassen MJ, Antal JM, Barna B, Divis LT, Meeker DP, Wiedemann HP (1996) Surfactant down regulates synthesis of DNA and inflammatory mediators in normal human lung fibroblasts. Am J Physiol (Lung Cell Mol Physiol 14 ) 270: L159 - L163.Google Scholar
  27. 27.
    Shah A, Church MK, Holgate ST (1995) Tumour necrosis factor alpha: a potential mediator of asthma. Clin Exp Allergy 25: 1038–1044.PubMedCrossRefGoogle Scholar
  28. 28.
    Bradding P, Feather IH, Wilson S, Bardin PG, Heusser CH, Holgate ST, Howarth PH (1993) Immunolocalisation of cytokines in the nasal mucosa of normal and perennial rhinitic subjects: The mast cell as a source of IL-4, IL-5 and IL-6 in human allergic mucosal inflammation. J Immunol 151: 3853–3865.PubMedGoogle Scholar
  29. 29.
    Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Heusser C, Howarth PH, Holgate ST (1994) Interleukin-4, -5, -6 and TNFa in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol 10: 471–480.PubMedGoogle Scholar
  30. 30.
    Piguet PF, Grau GE, Vassalli P (1990) Subcutaneous perfusion of tumour necrosis factor induces local proliferation of fibroblasts, capillaries, and epidermal cells or massive tissue necrosis. Am J Pathol 136: 103–110.PubMedGoogle Scholar
  31. 31.
    Laitinen LA, Laitinen A (1996) Remodeling of asthmatic airways by glucocorticosteroids. J Allergy Clin Immunol 97: 153–158.PubMedCrossRefGoogle Scholar
  32. 32.
    Stahle-Backdahl M, Parks WC (1993) 92-Kd gelatinase is actively expressed by eosinophils and stored by neutrophils in squamous cell carcinoma. Am J Pathol 142: 995–1000.Google Scholar
  33. 33.
    Teran LM, Carroll M, Frew AJ, Redington AE, Davies DE, Lindley I, Howarth PH, Church MK, Holgate ST (1996) Leukocyte recruitment following local endobronchial allergen challenge in asthma: its relationship to procedure and to airway interleukin-8 release. Am J Respir Crit Care Med 154: 496.Google Scholar
  34. 34.
    Redington AE, Madden J, Djukanovic R, Roche WR, Howarth PH, Holgate ST (1995) Transforming growth factor-beta levels in bronchoalveolar lavage are increased in asthma. J Allergy Clin Immunol 95 (ii): 377 (abstract).Google Scholar
  35. 35.
    Redington AE, Roche WR, Madden J, Frew AJ, Djukanovic R, Holgate ST, Howarth PH (1995) Basic fibroblast growth factor in asthma: immunolocalisation in bronchial biopsies and measurement in bronchoalveolar lavage fluid at baseline and following allergen challenge. Am J Respir Crit Care Med (abstract) 151: A702.Google Scholar
  36. 36.
    Walls AF, He S, Teran L, Buckley MG, Hung KS, Holgate ST, Shute JK, Cairns JA (1995) Granulocyte recruitment by human mast cell tryptase. Int Arch Allergy Immunol 107: 372–373.PubMedCrossRefGoogle Scholar
  37. 37.
    Cairns JA, Walls AF (1996) Mast cell tryptase is a mitogen for epithelial cells. Stimulation of IL-8 production and ICAM-1 expression. J Immunol 156: 275–283.PubMedGoogle Scholar
  38. 38.
    Walls AF, He S, Teran L, Holgate ST (1993) Mast cell proteases as mediators of vascular leakage and cell accumulation. J Allergy Clin Immunol 91: 256.Google Scholar
  39. 39.
    Lackie PM, Baker JE, Gunthert U, Holgate ST (1997) Expression of CD44 isoforms is increased in the airway epithelium of asthmatic subjects. Amer J Respir Cell Mol Biol 16: 14–22.Google Scholar
  40. 40.
    Rickard KA, Taylor J, Rennard SI, Spurzem JR (1993) Migration of bovine bronchial epithelial cells to extracellular matrix components. Am J Respir Cell Mol Biol 8: 63–68.PubMedGoogle Scholar
  41. 41.
    Sacco O, Romberger D, Rizzino A, Beckmann J, Rennard SI, Spurzem JR (1992) Spontaneous production of TGF-Beta 2 by primary cultures of bronchial epithelial cells: effects on cell behavior in vitro. J Clin Invest 90: 1379–1385.PubMedCrossRefGoogle Scholar
  42. 42.
    Romberger DJ, Beckmann JD, Claassen L, Ertl RF, Rennard SI (1992) Modulation of fibronectin production of bovine bronchial epithelial cells by transforming growth factor-beta. Am J Respir Cell Mol Biol 7: 149–155.PubMedGoogle Scholar
  43. 43.
    Lesur O, Arsalane K, Lane D (1996) Lung alveolar epithelial cell migration in vitro: modulators and regulation processes. Am J Physiol (Lung Cell Mol Biol 14 ) 270: L311 - L319.Google Scholar
  44. 44.
    Rickard KA, Shoji S, Spurzem JR, Rennard SI (1991) Migration of bovine bronchial epithelial cells to extracellular matrix components. Am J Respir Cell Mol Biol 4:440 118.Google Scholar
  45. 45.
    Spurzem JR, Sacco O, Veys T, Rickard K, Rennard SI (1992) TFF-beta increases expression of extra-cellular matrix receptors on cultured bovine bronchial epithelial cells. Am Rev Respir Dis 145: A668.Google Scholar
  46. 46.
    Shoji S, Rickard KA, Ertl RF, Robbins RA, Linder J, Rennard SI (1989) Bronchial epithelial cells produce lung fibroblast chemotactic factor: fibronectin. Am J Respir Cell Mol Biol 1: 13–20.PubMedGoogle Scholar
  47. 47.
    Koizumi S, Ertl R, Rennard S (1991) Bronchial epithelial cells stimulate fibroblast proliferation. Am Rev Respir Dis 143: A526.Google Scholar
  48. 48.
    Kawamoto M, Nakamura Y, Tate L, Ertl RF, Romberger DJ, Rennard SI (1992) Modulation of fibroblast type I collagen and fibronectin production by bronchial epithelial cells. Am Rev Respir Dis 145: A842.Google Scholar
  49. 49.
    Nakamura Y, Ertl RF, Kawamoto M, Tate L, Romberger D, Grossman G, Robbins RA, Rennard SI (1992) Bronchial epithelial cells modulate fibroblast proliferation: role of prostaglandin E2. Am Rev Respir Dis 145: A827.Google Scholar
  50. 50.
    Ertl RF, Valenti V, Spurzem JR, Kawamoto M, Nakamura Y, Veys T, Allegra L, Romberger DJ, Rennard SI (1992) Prostaglandin E inhibits fibroblast recruitment. Am Rev Respir Dis 145: A19.CrossRefGoogle Scholar
  51. 51.
    Bradley KH, Kawanami O, Ferrans VJ, Crystal RG (1980) The fibroblast of human lung alveolar structures: a differentiated cell with a major role in lung structure and function. Methods Cell Biol 21A: 37–64.CrossRefGoogle Scholar
  52. 52.
    Rennard SI, Romberger DJ, Sisson JH, Von Essen SG, Rubinstein I, Robbins RA, Spurzem JR (1994) Airway epithelial cells: functional roles in airway disease. Am J Respir Crit Care Med 150: S27 - S30.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Peter M. Hockey
  • Ratko Djukanović
  • William R. Roche
  • Steven T. Holgate

There are no affiliations available

Personalised recommendations