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Allergic Remodeling

Updated: April 2015
Originally Posted: December 2008

Phillip L. LiebermanOriginal author:
Phillip L. Lieberman, MD, FAAACI
Clinical Professor of Medicine & Pediatrics
Division of Allergy & Immunology
University of Tennessee College of Medicine
Germantown, Tennessee


Updated by:
John Oppenheimer, MD
Director of Clinical Research, Pulmonary and Allergy Associates
Denville, NJ, USA

Mauli Desai, MD
Assistant Professor of Medicine
Division of Allergy and Clinical Immunology
Icahn School of Medicine at Mount Sinai
Ardsley, NY, USA


Asthma is a chronic inflammatory disorder characterized by airway hyper-reactivity and reversible bronchoconstriction. This reversibility is lost in a subset of patients with asthma who develop permanent changes in the lung and an irreversible decline in FEV1. These permanent structural changes that occur in the lung are referred to as airway remodeling. Remodeling will manifest as a progressive increase in symptoms and corresponding decrease in bronchodilator responsiveness.

No single definition for airway remodeling exists. A good working definition, as written by Phil Lieberman in a previous WAO review, is: “A gradual but progressive and irreversible decline in airway function due to an inflammatory process that results in structural changes in the airway walls.”1

Mechanisms of airway remodeling

Remodeling of the airway involve all layers of the airway wall and can occur anywhere along the respiratory tract, from the large to the small airways.  The irreversible structural changes in the airway walls are characterized by the following:

  • Epithelial damage
  • Collagen deposition in sub-epithelial reticular basement membrane
  • Smooth muscle hyperplasia and hypertrophy/ increased smooth muscle mass
  • Destruction of elastic tissue
  • Mucus gland hypertrophy
  • Angiogenesis

The concept of the epithelial-mesenchymal trophic unit identifies the epithelium as key tissue, through which genetic and environmental factors influence the process of remodeling.2  Damaged epithelial cells can release profibrotic cytokines, such as EGF and TGF-beta, which leads to fibroblast proliferation and myofibroblast activation.  TGF-beta, IL-11, and IL-17 have been implicated in the formation of subepithelial fibrosis.3 Myofibroblasts, specialized cells with characteristics of both fibroblasts and myocytes, are likely key effector cells in subepithelial fibrosis as they produce smooth muscle actin, inflammatory mediators, and extracellular matrix proteins involved in tissue repair and remodeling.  Airway smooth muscle hypertrophy and hyperplasia lead to an increase in airway wall thickness. 

The pathologic changes above translates to the following physiologic consequences:

  • Decreased airway distensibility (stiffer airways)
  • Diminished elastic recoil
  • Progressive decline in FEV1, and FVC

Airway remodeling may lead to a subphenotype of asthma characterized by accelerated lung function decline and irreversible or only partially reversible airflow obstruction.  Clinical features of airway remodeling include an increase in symptoms such as dyspnea and decreased responsiveness to asthma therapy.  Although it has been assumed that remodeling contributes to bronchial hyper-reactivity, a study by Niimi et al. found a negative correlation between airway wall thickness and methacholine response.4  Therefore, the relationship between remodeling and the degree of bronchial hyper-reactivity remains ill defined.


Airway remodeling is likely a consequence of genetics with accompanying environmental factors.  Progressive, irreparable damage is suspected to be a result of the following:

  • Airway inflammation (triggers such as irritants, allergens, viruses)
  • Epithelial tissue injury
  • Abnormal repair mechanisms

It is accepted that chronic and recurrent bouts of inflammation lead to airway remodeling.  However, it cannot be presumed that severity of asthma will correlate with the degree of airway remodeling. In fact, some studies have shown that airway remodeling occurs even in patients with mild asthma and can begin as early as preschool age.5

A study by Grainge et al, found that compressive mechanical forces during episodes of bronchoconstriction may induce remodeling, independent on inflammation.6  The study groups that were repeatedly challenged with dust mite allergen or methacholine (eliciting bronchoconstriction alone without inflammation) had significant and similar levels of airway remodeling seen on bronchial biopsy compared with control groups.

It is difficult to predict which asthmatics will develop remodeling.  As noted earlier, there is evidence that shows this process begins as early as in childhood.  Risk factors that have been implicated include: lower initial FEV1, lower FEV1/FVC ratio, duration of asthma, male sex, and atopy.7


Airway remodeling is presumed to be present when serial measurements of post-bronchodilator FEV1 show a decline in lung function.

Other methods that have been used, but are most feasible in a study setting, include high resolution CT, bronchial biopsy, and endobronchial ultrasound. Quantitative multiple detector CT imaging allows for measurement of airway wall area (WA) and airway wall thickness (WT). WA and WT percentages have been shown to correlate with basement membrane thickening and possibly with FEV1 and bronchodilator responsiveness. Further evaluation of this diagnostic modality is needed. It may represent a non-invasive measure of airway remodeling that can potentially be used in a study setting as a diagnostic tool or as an endpoint for targeted therapy for airway remodeling.

Treatment & Prevention

Although early studies indicated that early intervention with ICS could impede the remodeling process,8-11 presently there is no convincing data to suggest that current therapies for asthma prevent or reverse the remodeling process. In fact, long-term intervention studies of ICS in childhood asthma have shown little or no effects on post bronchodilator FEV1.12-15 In the Childhood Asthma Management Program (CAMP) study, treatment with budesonide or nedocromil for four to six years did not improve lung function, as measured by post-bronchodilator FEV1 % of predicted value.12 A subsequent analysis of this cohort found that 25.7% of these children had a significant reduction in post-bronchodilator FEV1%, thus demonstrating an early start to progressive lung function decline despite treatment with ICS.14 In the full 5 year study period of the inhaled Steroid Treatment as Regular Therapy (START) trial, a large randomized 3 year study of patients with mild persistent asthma, post-bronchodilator FEV1% declined by an average of 2.22% irrespective of randomization to low dose ICS or placebo.13,16.

There may be therapeutic targets other than eosinophilic inflammation that may prove more successful in preventing this fibrotic process. Recent literature has highlighted the heterogeneity of asthma.17 Much of this heterogeneity appears to stem from the mediators associated with the inflammatory process, with some asthmatics having a largely eosinophilic process, while in others it is neutrophilic. This difference appears to be associated with multiple aspects of asthma, including: corticosteroid responsiveness, severity and likelihood of exacerbation. 18,19 Furthermore, there is some evidence described above that repeated bronchoconstriction independent of inflammation may contribute to this process. Thus, treatment aimed at maintaining airway caliper is worthy of further study.


Many questions remain regarding the pathogenesis and causes of airway remodeling. More research is needed to find out how and when this process begins, its natural history, and which patients are at risk. This is very important, as patients with permanent lung damage and irreversible airway obstruction seem to have worse long-term clinical outcomes. Once the causes and mechanisms of airway remodeling are better understood, we may discover new therapeutic targets for the prevention or reversal of airway remodeling.

Reading List

  1. Lieberman P. Allergic Remodeling. WAO website; 2008:Accessed April 1, 2015.
  2. Holgate ST, Holloway J, Wilson S, Bucchieri F, Puddicombe S, Davies DE. Epithelial-mesenchymal communication in the pathogenesis of chronic asthma. Proc Am Thorac Soc. 2004;1(2):93-98.
  3. Chakir J, Shannon J, Molet S, et al. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol. 2003;111(6):1293-1298.
  4. Niimi A, Matsumoto H, Takemura M, Ueda T, Chin K, Mishima M. Relationship of airway wall thickness to airway sensitivity and airway reactivity in asthma. Am J Respir Crit Care Med. 2003;168(8):983-988.
  5. Saglani S, Payne DN, Zhu J, et al. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med. 2007;176(9):858-864.
  6. Grainge CL, Lau LC, Ward JA, et al. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med. 2011;364(21):2006-2015.
  7. Rasmussen F, Taylor DR, Flannery EM, et al. Risk factors for airway remodeling in asthma manifested by a low postbronchodilator FEV1/vital capacity ratio: a longitudinal population study from childhood to adulthood. Am J Respir Crit Care Med. 2002;165(11):1480-1488.
  8. Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial. J Allergy Clin Immunol. 1992;90(1):32-42.
  9. Selroos O, Pietinalho A, Löfroos AB, Riska H. Effect of early vs late intervention with inhaled corticosteroids in asthma. Chest. 1995;108(5):1228-1234.
  10. Haahtela T, Järvinen M, Kava T, et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med. 1994;331(11):700-705.
  11. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med. 1994;88(5):373-381.
  12. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med. 2000;343(15):1054-1063.
  13. Busse WW, Pedersen S, Pauwels RA, et al. The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with budesonide in mild persistent asthma. J Allergy Clin Immunol. 2008;121(5):1167-1174.
  14. Covar RA, Spahn JD, Murphy JR, Szefler SJ, Group CAMPR. Progression of asthma measured by lung function in the childhood asthma management program. Am J Respir Crit Care Med. 2004;170(3):234-241.
  15. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006;354(19):1985-1997.
  16. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361(9363):1071-1076.
  17. Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet. 2006;368(9537):804-813.
  18. Kamath AV, Pavord ID, Ruparelia PR, Chilvers ER. Is the neutrophil the key effector cell in severe asthma? Thorax. 2005;60(7):529-530.
  19. Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD, Martin RJ. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med. 1997;156(3 Pt 1):737-743.


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