Remodeling in asthma and COPD – differences and similarities
Conflicts of interest
This article forms part of a supplement sponsored by GlaxoSmithKline. CM Sköld has received consultancy and Advisory Board fees from Boehringer-Ingelheim/Pfizer, Novartis, Sanofi-Aventis and GlaxoSmithKline, and lecture fees from AstraZeneca, Boehringer-Ingelheim, Pfizer and GlaxoSmithKline
C Magnus Sköld, MD, PhD, Department of Medicine, Division of Respiratory Medicine, Karolinska Institutet, Karolinska University Hospital Solna
SE-171 76 Stockholm, Sweden.
Tel: +46 8517 73905
Fax: +46 8312705
Background: Asthma and chronic obstructive pulmonary disease (COPD) are both inflammatory disorders. Diagnosis of these diseases is based upon limitation of expiratory airflow. The pathophysiological correlates to this impaired lung function are complex but they are associated with the development of structural changes in the airways and lung parenchyma. These remodeling processes differ between the two diseases. In asthma, airways obstruction is predominately located in the large airways, although recent studies indicate that inflammation and structural changes also is present in other compartments of the lungs. In COPD, remodeling of the small airways and lung parenchyma are the main correlates to the limitation of expiratory airflow. However, both asthma and COPD are heterogeneous disorders including various phenotypes and there is a considerable overlap between the two diseases.
Methods and Results: In the present review, airway remodeling in asthma and COPD will be discussed in three different compartments of the airways: large airways, small airways and lung parenchyma. Different inflammatory cells will be mentioned, as well as markers of remodeling.
Conclusion: In COPD and severe asthma, current anti-inflammatory pharmacotherapy does not restore lung function impairment fully. It is therefore recognized that research aiming to explore mechanisms of airway remodeling should be encouraged.
Please cite this paper as: Sköld CM. Remodeling in asthma and COPD – differences and similarities. Clin Respir J 2010; 4 (Suppl. 1): 20–27.
Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory diseases characterized by limitation of expiratory airflow. Acute asthma may be triggered by sensitizing stimulus, e.g. allergens, and symptoms of airflow limitation can mostly be treated with appropriate bronchodilators and glucocorticoids. In COPD, the major cause is a long-term exposure to cigarette smoke leading to persistent airflow limitation which responds poorly to available pharmacotherapy. Thus, both the exposure patterns and the clinical manifestations differ between asthma and COPD. There is, however, a considerable overlap between the disease; in particular severe asthma and COPD share similarities. The phenotype of severe asthma includes both physiological characteristics and inflammatory pattern that may be impossible to distinguish from COPD (1).
Remodeling can be defined as alterations of tissue structural components. It can occur during normal organ development but can also occur as a response to injury or inflammation. These changes may lead to difficulties in maintaining normal tissue function. Both asthma and COPD are characterized by structural changes, located in various parts of the airways and lung parenchyma and they differ for the two diseases entities.
In the present review, airway remodeling in asthma and COPD will be discussed, with focus on three different compartments of the airways: large airways, small airways and lung parenchyma. Inflammatory cells will be mentioned but mediators will not be discussed generally, because this is beyond the scope of this review. The text is accompanied by tables comparing markers of remodeling in asthma and COPD in the large airways (Table 1) and in the small airways/lung parenchyma (Table 2).
Table 1. Markers of remodeling in asthma and COPD – large airways
|Epithelial integrity||Damaged, denuded (?)||Preserved, metaplasia||(2, 7)|
|Goblet cells||++||+++ (in chronic bronchitis)||(9, 11)|
|Epithelial basement membrane thickening||+++||(+)||(6, 16–18, 26)|
|Smooth muscle mass||+++||(+)||(2, 10, 27–29)|
|Submucosal glands||+ to +++ (fatal disease)||+++ (bronchitis)||(9, 10, 12)|
|Inflammatory cells||Eosinophils, CD4+, mastcells (in severe asthma: neutrophils, CD8+)||Macrophages, neutrophils, CD8+, CD4+, (subsets of patients: eosinophils)||(1–3, 5, 6)|
Table 2. Markers of remodeling in asthma and COPD – small airways and lung parenchyma
|Goblet cells||?||++||(2, 26, 44)|
|Peribronchiolar fibrosis||+?||+++||(26, 29, 41, 73, 74)|
|Smooth muscle mass||++ (severe asthma)||(+)||(2, 29, 38, 39)|
|Loss of alveolar attachments||0||+++||(61)|
|Inflammatory cells – small airways||Eosinophils, T-cells, mastcells, (severe disease: neutrophils)||Neutrophils, T-cells, B-cells, macrophages||(33, 35–37, 40, 41, 43)|
|Inflammatory cells – lung parenchyma||Mastcells, eosinophils, macrophages (severe asthma)||CD4+, macrophages (emphysema)||(57, 58, 60)|
Most studies on large airways have been conducted using induced sputum or bronchial biopsies obtained by fiberoptic bronchoscopy. The type and amount of inflammatory cells in the large airways differs between asthma and COPD. Furthermore, severity of the disease, medications and exacerbations have an impact on the recruitment of inflammatory cells. In mild stable asthma, an increase in the number of CD4+ T-cells, eosinophils and mast cells have been reported (2). In mild stable COPD, an elevated number of CD8+ T-cells, macrophages and neutrophils have been observed. Neutrophils are, in particular, associated with COPD exacerbations and increased sputum production (3). Notably, the number of neutrophils in induced sputum correlates with the decline in forced expiratory volume in one second (FEV1) in smokers (4). In stable COPD, intraepithelial CD4+ and CD8+ T cells are elevated (5). A subset of COPD patients with a higher degree of reversibility has increased numbers of eosinophils (6). In severe and fatal asthma, the number of neutrophils, macrophages and CD8+ T-cells are elevated (1, 2) thereby resembling COPD.
Damage to and shedding of the airway epithelium is observed in bronchial biopsies in asthma. The shedded epithelial cell clusters have been described in sputum as ‘creola bodies’. It is however still under debate whether this is an artifact of the sampling procedure. Thus, the loss of surface epithelium in mild asthma is variable and in some studies it has not been significant different from controls (7). In other studies (8) a correlation between bronchial hyperresponsiveness and the degree of epithelial shedding have been observed. In COPD, squamous cell metaplasia and goblet cell hyperplasia and loss of ciliated epithelial cells are reported in the large airways (2).
Increased numbers of goblet cells is observed in chronic bronchitis (9). In fatal asthma as well as in chronic bronchitis, the number of mucus glands is increased. There are data supporting that this may not be the case in COPD with a marked emphysematous phenotype (10). In severe asthma, the airways can be obstructed by mucus. In patients who have died from asthma, the airways are occluded by mucus plugs. Even in mild to moderate asthma, there is a goblet cell hyperplasia and increased stored mucins in the airway epithelium (11). Lynne Reid calculated the relationship between airway wall thickness and the thickness of the mucus glands and demonstrated that this ratio (‘Reids index’) was increased in chronic bronchitis compared with normal controls (12). Interestingly ‘Reids index’ was also lower in patients with emphysema without sputum production compared with patients with chronic bronchitis, highlighting one aspect of COPD heterogeneity. It has been demonstrated that COPD-patients with chronic mucus hypersecretion have a more rapid loss of lung function compared with COPD patients with those who have no mucus secretion (13). Immunohistochemically, in bronchial biopsies, smokers with airways obstruction have more mucins, in particular MUC5AC and MUC5B, in their bronchial epithelium compared with smokers without airways obstruction and to normal controls (14, 15). Airway mucus in asthma is more viscous, forming mucin plugs, than mucus from COPD-patients. This suggests a biochemical difference in the composition of mucins between the two diseases (15). Such a difference may, in part, also be because of an increased contribution of plasma exudation in asthma compared with COPD.
Reticular basement membrane (RBM)
Thickening of the RBM has been observed in asthma. This phenomenon is more pronounced in non-atopic than in atopic asthmatics and it has been reported to show a positive correlation with asthma severity (16–18) even though there are studies that show no such correlation (19). RBM thickening occurs early in the asthmatic process (17) and it has also been described in children with asthma (20). It has been proposed that this type of remodeling may serve as a protective role diminishing the effect of smooth muscle contraction on airway narrowing (21, 22). RBM thickness in asthma correlates with the number of myofibroblasts (23) and fibroblasts (24) in the connective tissue and RBM thickness is also associated with a higher number of eosinophils in the bronchial mucosa (25). Thus, RBM thickening is a feature of severe asthma but it has also been described in perennial rhinitis (22). In COPD or in chronic bronchitis, some studies have shown no alteration in RBM thickness compared with healthy control subjects (26); whereas, other studies have shown a slight increase in the thickness compared with controls (18). Increased RBM thickness associated with eosinophils has also been described in COPD (6).
The smooth muscle mass in the large airways is increased in asthma and there is a relation between the amount and the severity of the disease (27, 28). This increase is because of both hyperplasia and hypertrophia of smooth muscle cells. There is also, however, an increased amount of extracellular matrix components located both within and outside the smooth muscle bundles (29, 30). In fatal asthma, there is a considerable increase in both glands and in smooth muscle bundles, in particular, in the larger bronchi (10). Severe persistent asthma is also associated with higher numbers of fibroblasts, an increase in collagen III, larger mucus glands and smooth muscle cells (27). Even in mild asthmatics, an increase in proteoglycan deposition in the large airways has been described (31). It seems that the smooth muscle cells, which are normally located deep in the submucosal tissue, have a much closer location to the epithelium in asthmatics (27). This may indicate that a dedifferentiation of smooth muscle cells occur leading to a migration of mesenchymal cells toward the epithelium, thereby supporting the hypotheses of plasticity of structural cells in the airways of asthmatics. In severe asthma, not only the numbers of smooth muscle cells but also the size of the individual cells is increased compared with controls, mild to moderate asthmatics and to patients with COPD. The increase in extracellular matrix components in conjunction with smooth muscle cells in asthma may affect airway wall compliance, resulting in a more ‘stiff’ tissue and limit the smooth muscle cell-induced airway narrowing (29). In COPD, there is no such increase in smooth muscle bundles in the large airways, although some earlier studies have shown slightly more smooth muscle compared with controls (2, 29).
Remodeling of the small (<2 mm) airways occurs both in asthma and in COPD. This compartment is difficult to access and most studies have been performed on surgical specimens or post-mortem examination of lung tissue, which may bias the results. In addition, many of the studies lack control material. Some investigators have used trans-bronchial biopsies (TBB) obtained via fiberoptic bronchoscopy. This method samples mostly the lung parenchyma and not exclusively the small airways.
By analyzing TBB from patients with severe steroid-dependent asthma, it was demonstrated that there were more inflammatory cells per mm2 in the small airways compared with large airways (32), and that this could be attributed to increased numbers of mast cells (33). The number of mast cells correlated positively to lung function suggesting a protective role of these cells in severe steroid-dependent asthma. Interestingly, in a recent study (34), a site-specific mast cell heterogeneity under ‘non-inflamed’ conditions was demonstrated which has to be taken into account when data from various diseases are interpreted. By analyzing lung tissue obtained through resection, a higher number of T-cells and eosinophils (35–37) in asthmatic small airways have been described. However, the referred tissue was obtained from smoking asthmatic patients undergoing surgery for suspected lung cancer; a fact that may influence the results.
The literature is sparse with regard to the description of structural changes in distal airways in asthma. Airway wall thickening and increase in smooth muscle mass, however, has been described in asthma, in particular in fatal disease (38, 39). This was combined with an increased proportion of vessels in the tissue. An increase in the number of goblet cells has also been proposed (2). However, the nature of small airway remodeling in asthma, in particular, the involvement of extracellular matrix components, needs to be determined in future studies,
There seems to be a differential distribution of inflammatory cells in smokers along the airway tree. For instance, the number of neutrophils and mast cells is higher in the small compared with the large airways (40). In COPD, it is believed that the major site of the airways obstruction is located in the small airways. Thus, the small airway wall thickening correlates with the expiratory airflow limitation in COPD (41). The same study was also able to demonstrate that the number of inflammatory cells, including neutrophils, macrophages, T- and B-cells in the small airways correlates with the severity of airways obstruction. Other studies have shown increased eosinophils and CD8+ T-cells in smokers regardless of airways obstruction (42). CD8+ T-cells have been reported to be increased in the small airways from patients with COPD and their number correlates inversely with lung function measured as FEV1(43). Furthermore, an increased number of goblet cells have been found in the bronchiolar epithelium both in COPD and in chronic bronchitis (44), and an increased MUC5AC and MUC5B (45). The biochemical composition and structure of the peribronchiolar fibrosis in COPD is largely unknown. There is also data supporting an increased smooth muscle mass in the small airways in COPD (2, 29).
It has been proposed that airway remodeling is driven by an abnormal cross-talk between the epithelium and the underlying mesenchymal cells and matrix in chronic airway disease such as asthma and COPD (46–49). According to this hypothesis, fibrosis of the small airways is a result of an impaired repair following an injury to the bronchiolar epithelium. This leads to the activation, proliferation and contraction of fibroblasts in the connective tissue and increased extracellular matrix production. Fibrosis should then be regarded as a defect interaction between epithelial and mesenchymal cells involving a number of growth factors such as TGFbeta. This model has also been discussed as a potential mechanism in other fibrotic disorders (50). As described above, inflammatory cells are present and may interact with the structural cells. For instance, experimental studies have shown that inflammatory cells and its mediators can stimulate fibroblast functions (51, 52).
To gain more knowledge of airway remodeling, it is important to have tools in order to monitor these processes. In asthma, large airway wall thickness have been quantified by high resolution computed tomography (HRCT) (53, 54) demonstrating that the large airway wall thickening correlates to severity of the disease. The concept that small airways constitute the major origin of the early airways obstruction in COPD, has lead to attempts to quantify small airway wall thickening by HRCT. In a study by Hasegawa et al. (55), it was demonstrated that there was a correlation between airway wall thickness, measured by HRCT and lung function in COPD. Most importantly, the correlation was stronger in smaller airways than in larger. New modalities, such as optical coherence tomography is also promising in this regard (56).
The lung parenchyma is the alveolar part of the lung where the gas exchange takes place. Our knowledge is sparse regarding inflammation and remodeling in this region of the lung in asthma. By using TBB in patients with nocturnal asthma, the number of eosinophils, CD4+ T-cells and macrophages were increased in alveolar tissue at the time of symptoms (57, 58). The degree of eosinophilic inflammation corrrelates positively with lung volumes in asthma (59). In COPD, there is an accumulation of neutrophils, macrophages, CD4+ and CD8+ T-cells in emphysematous tissue. In particular, the CD4+ subset seems to be associated with severe emphysema (60). Emphysema is defined as destruction of alveolar walls and interstitial tissue. This is exclusively present in COPD. The destruction of the alveolar walls results in fewer alveolar attachments which, in turn, contribute to the small airway narrowing in COPD, because this ‘suspension device’ of the small airways is defective. It has been shown that the number of alveolar attachments correlates to the inflammatory score in COPD (61).
Currently, it is believed that there are at least two major patophysiological mechanisms responsible for the development of emphysema: protease – antiprotease imbalance and apoptosis of structural cells (46). The proteinase – antiproteinase hypothesis, which is now well established, originates from an observation in the early 1960s describing that alpha-1-proteinase inhibitor deficiency in humans was associated with pulmonary emphysema (62). Simultaneously, experimental animal models revealed that instillation of proteases into the lung resulted in the development of emphysema (63, 64). Initially, the main focus was on neutrophil elastase and alfa-1 proteinase inhibitor. During recent years, the role of additional enzymes such as metalloproteinases and cysteine proteinases has also been recognized. The balance between proteinases and antiproteinases could be shifted toward excess proteinases by inflammatory responses and by an increased oxidative burden induced by i.e. cigarette smoke. In agreement with this concept, elevated concentrations of various proteinases in the lower respiratory tract have been described in COPD (65). The idea that emphysema is caused by apoptosis of endothelial cells was forwarded in the late 1950s (66). In animal models, the importance of vascular endothelial growth factor (VEGF) for the survival of endothelial cells has been stressed. Specifically, the inhibition of VEGF-receptor kinase results in emphysema (67) and VEGF-deficient mice develop emphysema-like structural changes (68). Furthermore, in lungs from patients with emphysema, there is less VEGF and VEGF-receptors (69).
Tissue composition in the lungs of patients with COPD has been investigated in a number of studies. Interestingly, in emphysema, collagen and elastin per weight unit, respectively, is increased compared with patients without emphysema (70–72). This suggests that besides destruction of the lung tissue, fibrotic mechanisms may occur in parallel.
Asthma and COPD are inflammatory disorders which both are diagnosed by limitation of expiratory airflow. The pathophysiological correlates to this impaired lung function are complex but are associated with the development of structural changes in the airways and lung parenchyma. These remodeling processes differ between the two diseases. In asthma, airways obstruction has been considered to be located predominately in the large airways. Recent studies, however, indicate that inflammation, and probably also structural changes, are also present in the small airways in asthma. In COPD, remodeling of the small airways and lung parenchyma are the main correlates for the limitation of expiratory airflow. It has to be stressed that asthma and COPD are heterogeneous disorders including various phenotypes, and there is a considerable overlap between two the diseases.
Tissue remodeling is an important feature in inflammatory pulmonary diseases. This is a consequence of a chronic, long-lasting injury and the structural changes have a significant impact on lung function impairment not only in COPD but also in asthma. Patients with COPD respond poorly to current pharmacological therapies as compared with asthma. It seems that the more distal in the lung the remodeling occur, the more irreversible it is to current treatment (Table 3). Our knowledge regarding mechanisms leading to tissue alterations has increased during the last 5–10 years but is still relatively limited. Both asthma and COPD are complex diseases with a high degree of heterogeneity with regard to a number of parameters such as extent/severity of disease, smoking, allergen exposure, reversibility and bronchitis symptoms. To what extent exacerbations contribute to remodeling processes is also largely unknown as is how different pharmacotherapies may influence this process. We do not know which aspects of airway remodeling that may be beneficial or whether the phenomenon is reversible. Further research including both experimental models and clinical investigations including well-characterized patients, may give answers to some of those questions.
Table 3. Remodeling in various lung compartment in asthma and COPD – impact on airwys obstruction and reversibility to current pharmacological treatment
|Small airways||+||+++||No (?)|
The main pharmacological treatment of asthma and COPD is based upon bronchodilators and glucocorticoids. In COPD and severe asthma, current pharmacotherapy does not restore lung function impairment fully. It is therefore increasingly recognized that research aiming to explore mechanisms of airway remodeling should be encouraged. This may lead to development of new therapeutic strategies in order to interfere with the biology of structural cells, hopefully resulting in at least a partial restoration of lung architecture.