Semin Respir Crit Care Med 2002; 23(4): 361-368
DOI: 10.1055/s-2002-34331
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Airway Remodeling in Asthma

Prescott G. Woodruff, John V. Fahy
  • Department of Medicine, University of California at San Francisco, and the Department of Cardiovascular Research Institute, University of California at San Francisco
Further Information

Publication History

Publication Date:
26 September 2002 (online)

ABSTRACT

Airway remodeling is a summary term for the pathological changes that occur in airway structure in allergic or suppurative airway diseases. Characteristic changes of airway remodeling in asthma include goblet cell hyperplasia, deposition of collagens in the basement membrane zone, increased size and number of microvessels in the submucosa, hyperplasia and hypertrophy of airway smooth muscle, and hypertrophy of submucosal glands. Some of these changes, such as goblet cell hyperplasia and subepithelial collagen deposition, are present even in mild asthma; other changes such as increases in airway smooth muscle and gland volume appear to be more characteristic of severe asthma. Airway narrowing, airway hyperresponsiveness, and mucus hypersecretion are all functional consequences of airway remodeling leading to clinical manifestations such as dyspnea, wheeze, sputum production, and susceptibility to asthma exacerbations. Noninvasive measures of remodeling are lacking, and monitoring the effects of treatment on remodeling has been difficult. For this reason relatively little is known about the effects of current asthma treatments on airway remodeling. As mechanisms of airway remodeling are developed, it is hoped that novel therapeutic targets will be identified. Treatments specifically targeting mediators of remodeling hold promise as treatments that could modify disease progression in asthma.

REFERENCES

  • 1 Lynch D A, Newell J D, Tschomper B A, Cink T M, Newman L S, Bethel R. Uncomplicated asthma in adults: comparison of CT appearance of the lungs in asthmatic and healthy subjects.  Radiology . 1993;  188 829-833
  • 2 Paganin F, Seneterre E, Chanez P. Computed tomography of the lungs in asthma: influence of disease severity and etiology.  Am J Respir Crit Care Med . 1996;  153 110-114
  • 3 Fahy J V, Corry D B, Boushey H A. Airway inflammation and remodeling in asthma.  Current Opinion in Pul Med . 2000;  6 15-20
  • 4 Laitinen L A, Laitinen A, Haahtela T. Airway mucosal inflammation even in patients with newly diagnosed asthma.  Am Rev Respir Dis . 1993;  147 697-704
  • 5 Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma.  N Engl J Med . 1998;  339 1194-1200
  • 6 Laitinen L A, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a β2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial.  J Allergy Clin Immunol . 1992;  90 32-42
  • 7 Lausen L C, Taudorf E, Borgeskov S. Fiberoptic bronchoscopy and bronchial mucosal biopsies in asthmatics undergoing long term high-dose budesonide aerosol treatment.  Allergy . 1988;  43 284-288
  • 8 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;  1988 883-889
  • 9 Jeffery P K, Godfrey R W, Adelroth E, Nelson F, Rodgers A, Johansson S A. Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma.  Am Rev Respir Dis . 1993;  145 890-899
  • 10 Hoshino M, Nakamura Y, Sim J J. Inhaled corticosteroid reduced lamina reticularis of the basement membrane by modulation of insulin-like growth factor (IGF)-I expression in bronchial asthma.  Clin and Exp Allergy . 1998;  28 568-577
  • 11 Olivieri D, Chetta A, Del Donno M. Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebo-controlled study.  Am J Respir Crit Care Med . 1997;  155 1864-1871
  • 12 Trigg C J, Manolitsas N D, Wang J. Placebo-controlled immunopathologic study of four months of inhaled corticosteroids in asthma.  Am J Respir Crit Care Med . 1994;  150 17-22
  • 13 Expert Panel Report II. Guidelines for the Diagnosis and Management of Asthma. National Asthma Education and Prevention Program. Bethesda, MD: National Institutes of Health; 1997. NIH Publication No. 97-4051
  • 14 Ordoñez C, Ferrando R, Hyde D M, Wong H H, Fahy J V. Epithelial desquamation in asthma: artifact or pathology?.  Am J Resp Crit Care Med . 2000;  162 2324-2329
  • 15 Fahy J V. Remodeling of the airway epithelium in asthma.  Am J Respir Crit Care Med. . 2001;  164(10 pt 2) S46-S51
  • 16 Soderberg M, Hellstrom S, Sandstrom T, Lundren R, Bergh A. Structural characterization of bronchial biopsies from healthy volunteers: a light and microscopical study.  Eur Resp J . 1990;  3 261-266
  • 17 Ordoñez C L, Khashayar R, Wong H H. Mild and moderate asthma is associated with goblet cell hyperplasia and abnormalities in mucin gene expression.  Am J Resp Crit Care Med . 2001;  163 517-523
  • 18 Huber H C, Koessler K K. The pathology of bronchial asthma.  Arch Intern Med . 1922;  30 689-760
  • 19 Houston J C, De Navasquez S, Trounce J R. A clinical and pathological study of fatal cases of status asthmaticus.  Thorax . 1953;  8 207-213
  • 20 Dunnill M S. The pathology of asthma with special reference to changes in the bronchial mucosa.  J Clin Pathol . 1960;  13 27-33
  • 21 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
  • 22 Lee H M, Takeyama K, Dabbagh K, Lausier J A, Ueki I F, Nadel J A. Agarose plug instillation causes goblet cell metaplasia by activating EGF receptors in rat airways.  Am J Physiol Lung Cell Mol Biol . 2000;  278 L185-L192
  • 23 Shim J J, Dabbagh K, Ueki I F. IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils.  Am J Physiol Lung Cell Mol Physiol . 2001;  280 L134-L140
  • 24 Alimann M Z, Piazza F M, Selby D M, Letwin N, Huang N, Rose M C. Muc-5/5ac mucin messenger RNA and protein expression is a marker of goblet cell metaplasia in murine airways.  Am J Resp Cell Mol Biol . 2000;  22 253-260
  • 25 Vinall L E, Fowler J C, Jones A L. Polymorphisms of human mucin genes in chest disease.  Am J Resp Cell Mol Biol . 2000;  23 678-686
  • 26 Rose M C, Gendler S J. Airway mucin genes and gene products. In: Rogers DF, Lethem DI, eds. Airway Mucus: Basic Mechanisms and Clinical Perspectives Boston, Mass: Birkhauser Verlag 1997
  • 27 Takeyama K, Fahy J V, Nadel J A. Relationship of epidermal growth factors to goblet cell production in human bronchi.  Am J Resp Crit Care Med . 2001;  163 511-516
  • 28 Takeyama K, Dabbagh K, Lee H M. Epidermal growth factor system regulates mucin production in airways.  Proc Natl Acad Sci . 1999;  96 3081-3086
  • 29 Hays S R, Woodruff P G, Khashayar R. Allergen challenge causes inflammation but not goblet cell degranulation in asthmatic subjects.  J Allergy Clin Immunol . 2001;  108 784-790
  • 30 Cormack D H. Ham's Histology.  9th ed. Philadelphia, PA: JB Lippincott 1987
  • 31 Roche W R, Beasley R, Williams J H, Holgate S T. Subepithelial fibrosis in the bronchi of asthmatics.  Lancet . 1989;  1(8637) 520-524
  • 32 Brewster C EP, Howarth P H, Djukanovic R, Wilson J, Holgate S T, Roche W R. Myofibrobalsts and subepithelial fibrosis in bronchial asthma.  Am J Resp Cell Mol Biol . 1990;  3 507-511
  • 33 Holgate S T, Lackie P M, Howarth P H. Invited lecture: activation of the epithelial mesenchymal trophic unit in the pathogenesis of asthma.  Int Arch Allergy Immunol . 2001;  124 253-258
  • 34 Evans M J, Van Winkle S L, Fanucchi M V, Plopper C G. Cellular and molecular characteristics of basal cells in airway epithelium.  Exp Lung Res . 2001;  27 401-415
  • 35 Ohno I, Nitta Y, Yamauchi K. Transfroming growth factor β1 (TGFβ1) gene expression by eosinophils in asthmatic airway inflammation.  Am J Resp Crit Care Med . 1996;  15 404-409
  • 36 Minshall E M, Leung D YM, Martin R J. Eosinophil-associated TGF-β1 mRNA expression and airways fibrosis in bronchial asthma.  Am J Resp Cell Mol Biol . 1997;  17 326-333
  • 37 Vignola A M, Chanez P, Chiappara G. Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchtis.  Am J Respir Crit Care Med . 1997;  156 591-599
  • 38 Munger J S, Harpel J G, Gleizes P, Mazzieri R, Nunes I, Rifkin D B. Latent transforming growth factor-beta: structural features and mechanisms of activation.  Kidney International . 1997;  51 1376-1382
  • 39 Chetta A, Foresi A, Del Donno M, Bertorelli G, Pesci A, Olivieri D. Airways remodeling is a distinctive feature of asthma and is related to severity of disease.  Chest . 1997;  111 852-857
  • 40 Boulet L P, Laviolette M, Turcotte H, Cartier A. Bronchial subepithelial fibrosis correlates with airway responsiveness to methacholine.  Chest . 1997;  112 45-52
  • 41 Chu H W, Halliday J L, Martin R J, Leung D YM, Szefler S J, Wenzel S E. Collagen deposition in large airways may not differentiate severe asthma from milder forms of the disease.  Am J Resp Crit CAre Med . 1998;  158 1936-1944
  • 42 Albertine K H, Williams M C, Hyde D M. Asthma. In: Murray JF, Nadel JA, Mason RJ, Boushey HA, eds. Textbook of Respiratory Medicine 3rd ed. Philadelphia, PA: WB Saunders 2000: 3-33
  • 43 James A, Carroll N. Airway smooth muscle in health and disease: methods of measurement and relation to fucntion.  Eur Resp J . 2000;  15 782-789
  • 44 James A L, Pare P D, Hogg J C. The mechanics of airway narrowing in asthma.  Am Rev Respir Dis . 1989;  130 242
  • 45 Heard B E, Hossain S. Hyperplasia of bronchial muscle in asthma.  J Pathol . 1973;  110 319-331
  • 46 Ebina M, Takahashi T, Chiba T, Motomiya M. Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma.  Am Rev Respir Dis . 1993;  148 720-726
  • 47 Hirst S J, Walker T R, Chilvers E R. Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma.  Eur Resp J . 2000;  16 159-177
  • 48 Hirst S J, Twort C H, Lee T H. Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype.  . 2000;  23 335-344
  • 49 Ma X, Wang Y, Stephens N L. Serum deprivation induces a unique hypercontractile phenotype of cultured smooth muscle cells.  Am J Physiol . 1998;  274 C1206-1214
  • 50 Halayko A J, Camoretti-Mercado B, Forsythe S M. Divergent differentiation paths in airway smooth muscle culture: induction of functionally contractile myocytes.  Am J Physiol . 1999;  276 L197-L206
  • 51 Fredburg J J. Airway smooth muscle in asthma: perturbed equilibria of myosin binding.  Am J Resp Crit Care Med . 2000;  161 S158-S160
  • 52 Fan T, Yang M, Halayko A, Mohapatra S S, Stephens N L. Airway responsiveness in two inbred strains of mouse disparate in IgE and IL-4 production.  Am J Respir Cell Mol Biol . 1997;  17 156-163
  • 53 Charan N B, Baile E M, Paré P D. Bronchial vascular congestion and angiogenesis.  Eur Resp J . 1997;  10 1173-1180
  • 54 Li X, Wilson J W. Increased vascularity of the bronchial mucosa in mild asthma.  Am J Resp Crit Care Med . 1997;  156 229-233
  • 55 Orsida B E, Li X, Hickey B, Thien F, Wilson J W, Walters E H. Vascularity in asthmatic airways: relation to inhaled steroid dose.  Thorax . 1999;  54 289-295
  • 56 Vrugt B, Wilson S, Bron A, Holgate S T, Djukanovic R, Aalbers R. Bronchial angiogenesis in severe glucocorticosteroid-dependent asthma.  Eur Resp J . 2000;  15 1014-1021
  • 57 Demoly P, Maly F E, Mautino G. VEGF levels in asthmatic airways do not correlate with plasma extravasation.  Clin Exp Allergy . 1999;  29 1390-1394
  • 58 Hoshino M, Takahashi M, Aoike N. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis.  J Allergy Clin Immunol . 2001;  107 295-301
  • 59 Orsida B E, Ward C, Li X. Effect of a long-acting beta2-agonist over three months on airway wall vascular remodeling in asthma.  Am J Resp Crit Care Med . 2001;  164 117-121
  • 60 Dunnill M S, Massarella G R, Anderson J A. 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
  • 61 Cluroe A D, Holloway L, Beasley R. Bronchial diverticulitis: a complication of bronchial asthma.  J Clin Path . 1988;  41 921-922
  • 62 Monckeberg J G. Zur pathologischen anatomie des bronchial asthmas.  Verhandl Deutsch Pathol Gesellsch . 1909;  14 173-180
  • 63 Cluroe A, Holloway L, Thomson K, Purdie G, Beasley R. Bronchial gland duct ectasia in fatal bronchial asthma: association with interstitial emphsyema.  J Clin Path . 1989;  42 1026-1031
  • 64 Louis R, Lau L CK, Bron A O, Roldaan A C, Radermecker M, Djukanovic R. The relationship between airway inflammation and asthma severity.  Am J Resp Crit Care Med . 2000;  161 9-16
  • 65 Woodruff P G, Khashayar R, Lazarus S C. Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma.  J Allergy Clin Immunol . 2001;  108 753-758
  • 66 Wenzel S E, Szefler S J, Leung D YM, Sloan S I, Rex M D, Martin R J. Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucorticoids.  Am J Respir Crit Care Med . 1997;  156(3, pt 1) 737-743
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