Search tips
Search criteria 


Logo of f1000medLatest ContentReportsReportsReports
F1000 Med Rep. 2010; 2: 74.
Published online 2010 October 12. doi:  10.3410/M2-74
PMCID: PMC2954424

Pulmonary remodeling in asthma


The inflammatory and immunologic processes responsible for asthma can produce permanently fixed obstructive lung disease unresponsive to medical therapy. This can be manifested clinically by the failure of a childhood asthmatic to reach full expected lung capacity at adulthood and by an accelerated decline in pulmonary capacity in adults. Recent studies have furthered our insight into the pathologic processes underlying these changes and the potential effects of therapy to prevent them.

Introduction and context

Twenty years ago, asthma was universally thought of as a reversible, obstructive pulmonary disease. It was not until the 1990s that the concept that asthma could produce irreversible obstructive changes was introduced [1]. A search of the medical literature revealed only two references to pulmonary remodeling in asthma between 1990 and 2000. Today, a similar search reveals 1477 references. The structural changes that produce this irreversibility are damage to the epithelium, smooth muscle hyperplasia and hypertrophy, the deposition of glycoproteins in the parenchyma, the destruction of elastin, neovascularization, a thickened sub-basement membrane, and mucous gland hyperplasia [2].

It has now become clear that a significant number of asthmatics are at risk for development of these permanent changes, and that the degree of impairment produced by the remodeling process is clinically significant [3-5]. As many as 25% of childhood asthmatics are at risk for impaired lung growth [4] and as many as 16% of adult asthmatics exhibit a permanent and accelerated decline in lung function [5]. These changes can amount to a reduction of a liter or more in forced expiratory volume in one second (FEV1) [6,7].

The underlying forces that drive the remodeling process consist of a panoply of inflammatory mediators that have destructive, restorative, and chemotactic properties and include, amongst many others, transforming growth factor beta, the metalloproteinases, eotaxin and other eosinophilic chemotactic agents, tryptase, histamine, elastase, and various interleukins (including IL-4, IL-5, IL-6, IL-9, and IL-13) [8-13]. The histologic changes characteristic of remodeling include smooth muscle hyperplasia, deposition of collagen and glycoproteins beneath the sub-basement membrane, goblet cell hyperplasia, airway epithelial cell proliferation and destruction, deposition of glycoproteins in the pulmonary parenchyma, and neovascularization.

Over the past several years, a number of risk factors have been identified that make it more likely that, in any given individual asthmatic, the remodeling process will occur [14,15]. These risk factors are listed in Table 1.

Table 1.
Factors associated with remodeling in asthma

Finally, it should be made very clear that the process of remodeling in asthma is distinct from the pathogenesis that results in a similar decline in lung function in chronic obstructive pulmonary disease/emphysema [16]. Although the rates of decline in FEV1 are similar in patients with fixed airflow obstruction caused by asthma to those with fixed airflow obstruction produced by emphysema, there are distinct differences between the two patient populations. Asthmatic subjects with fixed airway obstruction exhibit more exacerbations, higher exhaled nitric oxide levels, and higher sputum eosinophil counts. In contrast, sputum neutrophil counts, comorbidities, and a diminished diffusion capacity are more characteristic of patients with emphysema [16].

Obviously, the goal of investigations into the remodeling process in asthma is to gain insights that would hopefully allow us to prevent or reverse these changes. Over the past few years, our knowledge in this regard has increased considerably.

Recent advances

Advances have been made in our understanding of the ability of presently available treatments to favorably affect the remodeling process, allowing normal lung growth in children and preventing the accelerated decline in lung function in adults. Comparing clinical studies and other investigations into the mechanism(s) of the remodeling process, it has become evident that there may be distinct differences between the pathogenic mechanisms involved in the remodeling process in children versus those in adults and, therefore, distinct differences in their response to treatment.

Several recent clinical studies in children have been somewhat disappointing in terms of our present day ability to prevent the remodeling process and thus restore the normal rate of lung growth [17-19]. Taken as a whole, these three studies leave the distinct impression that inhaled corticosteroid therapy, although improving clinical parameters such as symptoms, pulmonary functions, and quality of life, do not seem to alter the potential for the diminished lung growth that occurs in childhood asthma. These studies are in contradistinction to older studies [20,21], as well as a more recent investigation [15], which demonstrated that the accelerated decline in lung function seen in many adult asthmatics can be diminished by regular administration of inhaled corticosteroids. In addition, this can be accompanied by improvement in the histopathology associated with the remodeling process in adults with this condition [20].

Perhaps the distinction between the failure to demonstrate enhanced lung growth in childhood asthma and the ability to diminish the accelerated decline in lung function in adult asthma could be related to differences in the pathogenesis of these two processes. It has been traditionally thought that the same remodeling process that produces an accelerated decline in lung function in adults also accounts for the diminished lung growth seen in childhood asthmatics. However, a recent investigation [22] casts doubt on this assumption. It has long been known that one of the characteristic features of the remodeling process in adults is the increased deposition of ground substances including fibronectin in the pulmonary parenchyma. It is thought that damage to the epithelium stimulates fibroblast activation below the basement membrane, and this results in the manufacture and deposition of a number of glycoproteins, including collagen.

In contrast, studies of bronchial epithelial damage in childhood asthma revealed that children with asthma, compared to healthy atopic control subjects and healthy nonatopic control subjects, demonstrate a reduced capacity of epithelial cells to manufacture fibronectin. Under normal circumstances, fibronectin assists in the repair process of bronchial epithelium. The authors found that childhood asthmatics had a diminished capacity to produce fibronectin as a result of an innate abnormality in bronchial epithelial cells. This contrasts sharply with the overproduction of fibronectin, as evidenced by deposits of this substance below the basement membrane, seen in the parenchyma of remodeled asthmatic airways. Fibronectin can be made by several different cell types that reside in the airways. These include fibroblasts, macrophages, and endothelial and epithelial cells. The precise source of the sub-basement membrane fibronectin seen in adult asthmatics is unknown, but presumably the majority is produced by fibroblasts. Of course, this difference between adults and children regarding the deposition of fibronectin may not explain differences noted between these two groups in their response to inhaled coticosteroids (see below), but it is at least suggestive of this possibility.

Implications for clinical practice

The findings noted above imply that in adults with asthma, early treatment with inhaled corticosteroids, administered on a daily basis and in sufficient doses, may have an impact on the remodeling process and therefore the accelerated decline in pulmonary function that occurs in a significant proportion of adult asthmatics.

Unfortunately, available studies to date have not shown that the use of inhaled corticosteroids favorably affects the failure of childhood asthmatics to reach full lung growth. These observations and in vitro studies on epithelial repair imply that there may be separate pathogenic mechanisms involved in the remodeling process in adults and children. Nevertheless, at least at this point in time in adults, corticosteroids seem to be the most potent weapon we have against pulmonary remodeling in asthma.


forced expiratory volume in one second


The electronic version of this article is the complete one and can be found at:


Competing Interests

The author declares that he has no competing interests.


1. Bousquet J, Chanez P, Lacoste JY, White R, Vic P, Godard P, Michel FB. Asthma: a disease remodeling the airways. Allergy. 1992;47:3–11. doi: 10.1111/j.1398-9995.1992.tb02242.x. [PubMed] [Cross Ref]
2. Bai TR. Evidence for airway remodeling in chronic asthma. Curr Opin Allergy Clin Immunol. 2010;10:82–6. [PubMed]
3. Murray C. Can inhaled corticosteroids influence the natural history of asthma? Curr Opin Allergy Clin Immunol. 2008;8:77–81. doi: 10.1097/ACI.0b013e3282f41769. [PubMed] [Cross Ref]
4. Covar RA, Spahn JD, Murphy JR, Szefler SJ, Childhood Asthma Management Program Research Group Progression of asthma measured by lung function in the childhood asthma management program. Am J Respir Crit Care Med. 2004;170:206–7. doi: 10.1164/rccm.200308-1174OC. [PubMed] [Cross Ref]
5. Vonk JM, Jongepier H, Panhuysen CIM, Schouten, JP, Bleecker ER, Postma DS. Risk factors associated with the presence of irreversible airflow limitation and reduced transfer coefficient in patients with asthma after 26 years of follow-up. Thorax. 2003;58:322–7. doi: 10.1136/thorax.58.4.322. [PMC free article] [PubMed] [Cross Ref]
6. Broide DH. Immunologic and inflammatory mechanisms that drive asthma progression to remodeling. J Allergy Clin Immunol. 2008;121:560–70. doi: 10.1016/j.jaci.2008.01.031. [PMC free article] [PubMed] [Cross Ref]
7. James AL, Wenzel S. Clinical relevance of airway remodeling in airway diseases. Eur Respir J. 2007;30:134–55. doi: 10.1183/09031936.00146905. [PubMed] [Cross Ref]
8. Gagliardo R, La Grutta S, Chanez P, Profita M, Paterno A, Cibella F, Bousquet J, Viegi G, Gjormarkaj M. Non-invasive markers of airway inflammation and remodeling in childhood asthma. Pediatr Allergy Immunol. 2009;20:780–90. doi: 10.1111/j.1399-3038.2009.00945.x. [PubMed] [Cross Ref]
9. Walters EH, Soltani A, Reid DW, Ward C. Vascular remodeling in asthma. Curr Opin Allergy Clin Immunol. 2008;8:39–43. doi: 10.1097/ACI.0b013e3282f42696. [PubMed] [Cross Ref]
10. Warner S, Knight D. Airway modeling and remodeling in the pathogenesis of asthma. Curr Opin Allergy Clin Immunol. 2008;8:44–8. doi: 10.1097/ACI.0b013e3282f3b5cb. [PubMed] [Cross Ref]
11. Riedl M, Nel A. Importance of oxidative stress in the pathogenesis and treatment of asthma. Curr Opin Allergy Clin Immunol. 2008;8:49–56. doi: 10.1097/ACI.0b013e3282f3d913. [PubMed] [Cross Ref]
12. Hassan M, Jo T, Risse P-A, Tolloczko B, Lemiere C, Olivenstein R, Hamid Q, Martin JG. Airway smooth muscle remodeling is a dynamic process in severe long-standing asthma. J Allergy Clin Immunol. 2010;125:1037–1045. doi: 10.1016/j.jaci.2010.02.031. [PubMed] [Cross Ref]
13. Pascual RM, Peters SP. The irreversible component of persistent asthma. J Allergy Clin Immunol. 2009;124:883–90. doi: 10.1016/j.jaci.2009.09.047. [PubMed] [Cross Ref]
14. Brinke AT. Risk factors associated with irreversible air flow obstruction in asthma. Curr Opin Allergy Clin Immunol. 2008;8:63–9. doi: 10.1097/ACI.0b013e3282f3b5b5. [PubMed] [Cross Ref]
15. O’Byrne PM, Pedersen S, Lamm CJ, Tan WC, Busse WW, START Investigators Group Severe exacerbations and decline in lung function in asthma. Am J Respir Crit Care Med. 2009;179:19–24. doi: 10.1164/rccm.200807-1126OC. [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Teal Hallstrand 30 Jan 2009
16. Contoli M, Baraldo S, Marku B, Casolari P, Marwick JA, Turato G, Romagnoli M, Caramori G, Saetta M, Fabbri LM, Papi A. Fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease: 5-year follow-up. J Allergy Clin Immunol. 2010;125:830–837. doi: 10.1016/j.jaci.2010.01.003. [PubMed] [Cross Ref]
17. Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A, IFWIN Study Team Secondary prevention of asthma by the use of inhaled fluticasone propionate in wheezy infants (IFWIN): double-blind, randomized, controlled study. Lancet. 2006;368:754–62. doi: 10.1016/S0140-6736(06)69285-4. [PubMed] [Cross Ref]
18. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, Bacharier LB, Lemanske RF, Strunk RC, Allen DB, Bloomberg GR, Heldt G, Krawiec M, Larsen G, Liu AH, Chinchilli VM, Sorkness CA, Taussig LM, Martinez FD. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006;354:1985–1997. doi: 10.1056/NEJMoa051378. [PubMed] [Cross Ref] F1000 Reports 6.4 Must Read
Evaluated by Johannes Wildhaber 29 Jun 2006, Michael Kabesch 26 Jul 2006
19. Bisgaard H, Hermansen M, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodes of wheezing. N Engl J Med. 2006;354:1988–2005. doi: 10.1056/NEJMoa054692. [PubMed] [Cross Ref] F1000 Reports 6.0 Must Read
Evaluated by Marzena Krawiec 01 Jun 2006
20. Sont JK, Willems LNA, Bel EH, van Krieken JHJM, Vandenbroucke JP, Sterk PJ, AMPUL Study Group Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. Am J Respir Crit Care Med. 1999;159:1043–51. [PubMed]
21. Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohisson SV, Ullman A, Lamm CJ, O’Byrne PM, START Investigators Group Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet. 2003;361:1071–6. doi: 10.1016/S0140-6736(03)12891-7. [PubMed] [Cross Ref]
22. Kicic A, Hallstrand TS, Sutanto EN, Stevens PT, Kobor MS, Taplin C, Pare PD, Beyer RP, Stick SM, Knight DA. Decreased fibronectin production significantly contributes to dysregulated repair of asthmatic epithelium. Am J Respir Crit Care Med. 2010;181:889–98. doi: 10.1164/rccm.200907-1071OC. [PMC free article] [PubMed] [Cross Ref]

Articles from F1000 Medicine Reports are provided here courtesy of Faculty of 1000 Ltd