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Imperial College London at the Royal Brompton Hospital, London, United Kingdom
Correspondence and requests for reprints should be addressed to Professor Peter K Jeffery, FRCPath, D.Sc., Ph.D., M.Sc., Lung Pathology Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail: p.jeffery{at}imperial.ac.uk
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ABSTRACT |
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 TOP ABSTRACT REMODELINGINFLAMMATIONOVERLAP BETWEEN ASTHMA AND...REFERENCES |
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Key Words: airways • chronic bronchitis • emphysema • inflammation • remodeling
Asthma and chronic obstructive pulmonary disease (COPD) are relatively nonspecific clinical terms used to describe two differ-ing patterns of airflow obstruction with respect to reversibility, whether spontaneous or in response to treatment. Both are chronic inflammatory conditions of the lung associated with alterations of structural components (1, 2). We now appreciate that there are contrasting predominant patterns of inflammatory cells and structural change, at least when comparison is made between lung tissue obtained from nonsmokers with mild asthma and smokers with mild to moderate COPD, selected from polar ends of the clinical spectrum of reversibility and in a stable phase of their disease (3). However, asthma and COPD are not single entities: each has a spectrum of reversibility and, in many patients, there is, as yet, an unappreciated "overlap" between them. This review summarizes the differences between these diseases with regard to structural changes and patterns of inflammation, and it considers the similarities that develop when these conditions become severe and when there are exacerbations. It gives three specific examples of the overlap between asthma and COPD.
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REMODELING |
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TOPABSTRACTREMODELINGINFLAMMATIONOVERLAP BETWEEN ASTHMA AND...REFERENCES |
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There are usually several components to the remodeling process, and the predominant anatomic focus of these changes is broadly different. In COPD, the structures most affected are the lung parenchyma (in emphysema) and small airways (thickening, fibrosis, loss of alveolar-bronchiolar attachments, and stenoses), whereas in asthma, the larger, more proximal airways are usually most affected (e.g., wall thickening and smooth muscle mass enlargement).
Epithelial Injury
Damage to and shedding of airway surface epithelium are often noted in histologic studies of individuals with asthma (Figure 1). There are clusters of sloughed epithelial cells (referred to as Creola bodies) in asthmatic sputa, increased numbers of epithelial cells in bronchoalveolar lavage fluid, and loss of the surface epithelium in biopsy specimens (4, 5). Aggregations of platelets together with fibrillary material, thought to be fibrin, have been observed in association with the damaged surface (5). In patients with asthma with varying severity of disease, the greater the loss of surface epithelium in biopsy specimens, the greater the degree of airway responsiveness (5). However, the loss of epithelium observed in biopsies of individuals with mild asthma is highly variable and an unreliable end point for determination of extent of injury or the response to treatment (6). Epithelial loss is less often observed in bronchial biopsies taken from smokers with bronchitis or COPD, in which goblet cell hyperplasia and squamous metaplasia (Figure 2) are often seen (3).
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RBM Thickness
Homogeneous thickening and hyaline appearance of the subepithelial lamina reticularis or RBM is pathognomic of asthma (Figure 1), albeit the thickening is greater in atopic than nonatopic forms of asthma (9, 10). RBM thickening has been reported to show a positive correlation with airway hyperresponsiveness, the frequency of asthma attacks, and the numbers of fibroblasts and "myofibroblasts" that lie external and adjacent to it (11–13). The thickening is not found in smokers with chronic bronchitis or COPD (see Table 1 and compare Figures 1 and 2). The reticular component of the basement membrane, so highly characteristic of the human (and monkey) but not of laboratory rodent airways, is not yet developed in the fetus (at least up to 18 weeks of gestation) (14), but rather forms later in early childhood, even in normal, healthy individuals. Relative to the norm, RBM thickening occurs early in the asthma process (15), even before asthma is diagnosed (16). We have reported recently that the RBM thickening is not apparent in symptomatic infants with reversible airflow obstruction until sometime after 24 months of age (17). However, it is significantly thicker in older children, 6 to 16 years old, with severe asthma as compared with child control subjects without asthma (and even compared with healthy adult control subjects) (15). Interestingly, the thickness in children with asthma, adults with mild asthma, and adults with severe asthma is similar (i.e., the RBM is already maximally thickened in children between the ages of 6 and 16 years of age). The thickening is present even in children with mild asthma (18). Moreover, we find no correlation between RBM thickness and either symptom duration for children with asthma or age for all individuals with asthma (15). The lack of association with duration of disease has also recently been demonstrated in adults with asthma (19).
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Interstitial Collagen
Interstitial collagen lies deep to the RBM. Although the RBM shares epitopes in common with interstitial collagen, it differs in its ultrastructure and fibrillar organization. The reticular (argyrophilic) fibrils are thinner and show less obviously the 65-nm periodicity banding that is characteristic of interstitial collagen, and they form a meshwork rather than the wavy bundles of parallel fibrils of interstitial collagen. For these reasons and the lack of progressive thickening of the RBM in asthma, the author's bias is to reject the term "subepithelial fibrosis" when this is applied to the thickening of the reticular layer in asthma. In contrast, an increase in the amount of interstitial collagen (forming scar tissue), referred to as airway wall fibrosis, is generally considered a feature of the airways (especially "small" airways) in smokers who develop COPD (24–26). In the parenchyma, the current definition of emphysema excludes the presence of obvious fibrosis, yet it is now known that fibrosis may also occur even in the presence of alveolar wall loss (27, 28). In COPD, the appearance of the fenestrae of "microscopic emphysema" and subsequent enlargement of alveolar spaces, distal to the terminal bronchiolus, may represent the consequence of lung injury and a failure of adequate repair rather than of alveolar wall destruction per se. Thus, the focal fibrosis that is identified in some cases of emphysema may represent the remainder of a repair process.
The interpretation of the data with respect to increases in the amounts of airway wall interstitial collagen in mild asthma are debated. However, with increasing severity of asthma there are increases in the area of the mucosa in a biopsy staining for collagen (29). Recent studies of bronchial biopsies obtained from patients with severe persistent asthma support this. In addition, they have demonstrated that there is increased deposition of subepithelial collagen type III together with a higher number of fibroblasts than in milder forms of asthma and also compared with large airway biopsies of patients with COPD (30). However, other authors report no such relationship with severity (31). Our own findings in mild allergic asthma show no differences compared with normal, healthy individuals in either collagen or elastic tissue (32), but our data contrast with the reported loss of elastic tissue in patients who died after an acute attack of asthma (33).
Angiogenesis
Dilatation of bronchial mucosal blood vessels, congestion, and wall edema are consistently reported features of fatal asthma. These characteristics can account for considerable swelling and stiffening of the airway wall (34–36). There are indications that the increased proportion of the wall occupied by vessel may be due in part to a proliferation of bronchial vessels (angiogenesis) (37). Although angiogenesis has been reported in mild asthma (38), it is particularly marked in severe corticosteroid-dependent asthma (39). It is unknown whether these changes are the consequence of chronic allergic inflammation or are due to the response to chronic (or latent) viral, mycoplasma, or bacterial infection. While proliferation of the bronchial vasculature is a feature of bronchiectasis and occurs in response to infection, changes to the bronchial vasculature have not yet been reported as a particular feature of COPD (40).
Enlargement of Bronchial Smooth Muscle Mass
Bronchial smooth muscle is arranged in a geodesic pattern, encircling the airway as two opposing spirals. Thus, when muscle contracts, it not only constricts but also shortens the airway. This may be important, because any factor that stiffens the airway, such as increased RBM thickness, increased collagen deposition, vascular congestion, or edema, will tend to resist airway shortening (34) and will likely resolve in favor of airway constriction in place of airway shortening (1).
The percentage of the bronchial wall occupied by bronchial smooth muscle is increased in fatal asthma: approximately 12% of the airway wall in segmental bronchi comprises muscle compared with about 5% in normal subjects. Hogg and colleagues (41, 42) have confirmed this trend in airways larger than 2 mm in diameter and demonstrated a two- to fourfold increase over normal in the area of the wall occupied by bronchial smooth muscle. The increase is fourfold in older patients with a longer duration of disease and twofold in younger cases of fatal asthma (19). The absolute increase in muscle mass is reported to be particularly striking in large intrapulmonary bronchi of lungs obtained after a fatal attack, compared with that seen in subjects with asthma dying of other causes (43). Occasionally, we have observed that large areas (> 85%) of a bronchial biopsy may be occupied by subepithelial muscle bundles in individuals with asthma hospitalized for a severe exacerbation (P. K. Jeffery, unpublished data). Two recent studies of bronchial biopsies, one in severe asthma and another in mild asthma, confirm this impression. In severe asthma, the distance of muscle to the epithelial RBM is reduced by comparison with biopsies obtained from patients with milder asthma or COPD (30), supporting the hypothesis that airway smooth muscle, normally present deep in the submucosa, may de-differentiate and migrate through the mucosa toward the epithelium (1, 44). In mild asthma, the volume of the biopsy subepithelium occupied by airway smooth muscle was at least 50% greater than in healthy subjects (45).
One systematic study has described changes in large-airway dimensions in relation to the lung function of patients with COPD (42). Alterations in large-airway smooth muscle mass have not been observed in COPD, and there is no correlation between muscle mass and airflow limitation. Studies of small airways in COPD have, however, demonstrated a relatively small but significant increase in airway wall smooth muscle and show a correlation between increased thickness and reduced FEV1 (46).
Several mechanisms may contribute to the increased smooth muscle mass in asthma: muscle fiber hyperplasia (47–49), hypertrophy (50, 51), or myocyte de-differentiation and migration in the form of myofibroblasts or fibromyocytes (1, 44). Although the data of Benayoun and coworkers in severe asthma show an increase of myocyte size and support the first hypothesis (30), the recent data of morphometry and gene expression profiling in mild asthma indicate that it is an increase of myocyte number rather than cell size that contributes most to the increased mass of bronchial muscle (45). Our original report considered that the fibroblast was a likely origin of the allergen-induced myofibroblast, and there is recent in vitro work to support this (52). However, the author's hypothesis is that in response to allergen challenge in asthma, there is de-differentiation of existing smooth muscle myocytes (the cells then are best referred to as "fibromyocytes"), and the cells migrate to a subepithelial site where they form new muscle of abnormal phenotype and abnormal function (1). In this respect, the epithelial injury and smooth muscle response in asthma parallels the findings of the response to endothelial injury and the associated changes and migration of vascular smooth muscle in atheroma. In support of the hypothesis, the capacity of airway (i.e., tracheal) smooth muscle myocytes to migrate has been demonstrated (53).
Hypersecretion
Many individuals with asthma suffer from excessive production of mucus that, admixed with the inflammatory exudate, forms highly tenacious plugs that block the airways and are exceedingly difficult to clear by cough (54, 55). There is clearly a component of mucus to these secretions, but the additional contribution by inflammatory cells and their secretory products in asthma may explain the particularly sticky nature of these secretions compared with the intraluminal mucus of chronic bronchitis.
Epithelial goblet cells and mucus-secreting submucosal glands are the major sources of luminal mucus. Goblet cell hyperplasia is a feature of the large airways in both asthma (56, 57) and chronic bronchitis (58). Goblet cells are normally absent or sparse in airways less than 2 mm in diameter (i.e., small bronchi and bronchioli), but they appear and increase in number in these peripheral airways in COPD (58, 59), a process referred to as mucous metaplasia.
Whether mucous metaplasia also occurs in asthma is debated. Some investigators suggest that the mucus found at this peripheral anatomic site may be aspirated from the larger airways rather than produced locally (56). However, the work of Shimura and colleagues is persuasive and indicates that mucous metaplasia is also a feature of asthma when goblet cell degranulation is widespread during a fatal attack, leading to the release of co-pious amounts of mucus that may remain adherent to the goblet cells (57).
Submucosal gland hypertrophy is also seen to about the same extent in both asthma and COPD. There are serous and mucous secretory units (acini) in the glands, and there is a single report that, although the normal proportions of serous to mucous acini are retained in asthma, there is a disproportionate increase of mucous acini and loss of serous acini in chronic bronchitis (60). As the serous acini contribute a variety of antibacterial substances, including lysozyme, lactoferrin, and the secretory component of secretory IgA, their reduction during the remodeling process in chronic bronchitis may be relevant to the apparent ease with which bacteria chronically colonize the respiratory tract.
However, gland hypertrophy per se is poorly associated with mucus hypersecretion (i.e., production of sputum), whereas inflammation in and around the acini is a better predictor of hypersecretion (61). This highlights the importance of inflammation, which may drive not only symptoms but also many of the processes associated with remodeling.
Some or all structural changes (Table 2) may be responsive to corticosteroid therapy, either directly through effects on the remodeling process per se or indirectly through the effects of steroids on the inflammation that is thought to drive remodeling.
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INFLAMMATION |
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B (62) and 15-lipoxygenase (63, 64). However, immunohistology of bronchial biopsies demonstrates differences in the predominant phenotypes of inflammatory cells that comprise the cellular components of inflammation. Bronchial biopsies of the large-airway mucosa obtained from nonsmokers with mild, stable, and allergic asthma have increased numbers of activated CD4+ (T-helper) lymphocytes, a predominance of the type 2 T-helper regulatory cytokines IL-4 and IL-5, and upregulation of eosinophil chemoattractants, including eotaxins and RANTES, and the associated tissue eosinophilia. Mast cells are reported to increase in number (3, 65), and their increase in airway smooth muscle in asthma, but not in that of "eosinophilic bronchitis," has led to the hypothesis that the clinical expression of asthma is the result of a mast cell myositis (66).
In contrast, the chronic inflammation of smokers with mild, stable COPD is predominantly of tissue CD8+ cells (likely to be T-suppressor/cytotoxic lymphocytes), a consequent low ratio of CD4+ to CD8+ cells, and increased numbers of CD68+ monocyte/macrophages and, variably, neutrophils (67, 68), the last associated with increased sputum IL-8 (69). Moreover, there is an inverse correlation between CD8+ cells and FEV1% of predicted in large airways, and the association becomes stronger in small airways and lung parenchyma, the main sites responsible for airflow obstruction in COPD (70, 71). The predominance of the CD8+ cell population is also detected in the adventitia of pulmonary vessels and lymph nodes draining the lung in COPD (72). There is emerging evidence for the presence of a type 1 profile of cells and regulatory cytokines in COPD, as evidenced by the increased numbers of CXCR3+ cells associated with interferon-
(73) (Table 3).
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Severe Disease
Increasing severity of COPD is associated with increased numbers of inflammatory cells in the conducting airways (75), and in the lung parenchyma increasingly severe emphysema is also associated with an amplification of the inflammatory response, especially of alveolar macrophages (76). Apoptosis may also be important in the destruction of parenchymal tissue in COPD, because there is evidence for increased apoptosis both in humans and in experimental animal models of emphysema (77, 78). Bronchial biopsy neutrophilia is not a feature of either mild COPD or asthma. However, in COPD, neutrophilia appears to contribute to the inflammation present in the airway lumen and is detected by analyses of bronchoalveolar lavage fluid and sputum, particularly as disease becomes more severe (79, 80). Both tissue and sputum neutrophilia are also features of severe steroid-refractory and persistent asthma (81, 82). In a recent biopsy study of severe asthma, there were also increased numbers of fibroblasts that correlated inversely with pre- and postbronchodilator FEV1 (30). Moreover, inflammation of the small airways, in which there is an inner-wall neutrophilia and an increase in mast cells in the outer wall, is also reported in severe asthma (83). An increased number of CD8+ cells has been reported in fatal asthma, which contrasts with the CD4+ predominance in mild disease (84) and is more similar to the pattern found in mild to moderate COPD.
Exacerbations
In severe exacerbations of asthma or COPD, the numbers of neutrophils are significantly increased in both sputum and bronchial biopsies compared with stable disease (Table 4). CD45+ cells are increased in both large and small airways. Biopsies of patients with COPD hospitalized and intubated in order to treat a severe exacerbation demonstrate an approximately 100-fold increase of neutrophil numbers compared with the stable phase of the disease (85). In severe exacerbations of asthma there is also a rise in the numbers of neutrophils (Y.-S. Qiu and colleagues, unpublished data). Neutrophil recruitment into airways in both conditions is partially the result of chemoattraction by neutro-phil chemokines, including IL-8 (now known as CXCL8) and epithelial-derived neutrophil attractant-78 (CXCL5)(85). CXCL8 is well known as a potent chemoattractant and activating cytokine for neutrophils and, to a lesser extent, for eosinophils. Endothelial cells, fibroblasts, epithelial cells, alveolar macrophages, and neutrophils are able to release CXCL8 in response to specific stimuli (e.g. tumor necrosis factor-
, IL-1, and endotoxin). It is believed that these chemokines attract neutrophils via their interaction with specific receptors on the cell surface, namely CXCR1 and CXCR2. Both receptors are highly expressed on neutrophils and macrophages and have been demonstrated to play functionally different roles on human neutrophils in vitro. The receptors are also found to be expressed on activated T lymphocytes, mast cells, dendritic cells, basophils, and eosinophils.
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Although tissue eosinophilia is normally a characteristic of mild asthma, in mild exacerbations of bronchitis eosinophils can also increase in number, not only in bronchial tissue but also in sputum and bronchoalveolar lavage fluid (86). The eosinophilia is accompanied by a marked recruitment of tissue neutrophils and with increased expression of the cytokine tumor necrosis factor-. In asthma, the infiltration of tissue by eosinophils is the end result an allergic reaction to allergen exposure, with memory T-helper cells regulating the specificity of the response. T-helper cells probably orchestrate the sequence of events via the production and secretion of interleukins, notably IL-4 and IL-5, which, although the cells that produce them are present, are not significantly increased in exacerbations. Although the eosinophil chemoattractant RANTES is markedly increased, eotaxin and monocyte chemoattractant protein-4 are not (87). IL-4 has also been demonstrated in abundance in association with submucosal glands of patients with chronic bronchitis in a stable phase of their disease (88). The most striking finding associated with an exacerbation in mild COPD is the upregulation of the eosinophil chemoattractant RANTES in both inflammatory and epithelial cells of the bronchial mucosa. The significant positive relationship between RANTES and tissue eosinophilia supports a role for this mechanism in the initiation of the tissue eosinophilia in a population of bronchitics with a recent exacerbation (89). Sputum IL-6 has also been shown to increase during exacerbations of patients with COPD, and raised sputum levels of IL-8, measured during the stable phase of disease, are associated with relatively high exacerbation frequency (90).
Exacerbations of mild COPD are associated with an increased number of CD4+ cells, and there is a relative fall in the CD8:CD4 ratio, due primarily to the increase of the CD4+ subset. The current working hypothesis is that an exacerbation due to viral infection of airway surface epithelium in smokers with bronchitis induces a marked upregulation of epithelial RANTES (89). RANTES, acting through CCR3 receptors, is most responsible for the recruitment of tissue eosinophils in virally induced exacerbations of bronchitis, but it also, via CCR3 and CCR4 receptors, recruits CD4+ memory cells with consequent reduction of the normally high CD8:CD4 ratio present in stable disease. There is evidence that RANTES acts synergistically with CD8+ cytolytic cells to enhance Fas ligand–dependent apoptosis of virally infected cells. Thus, when CD8+ cells predominate, exacerbations and increased RANTES may promote CD8+-mediated tissue damage. Increased frequency of viral exacerbations may thus destroy airway and alveolar tissue directly, encouraging the development of microscopic emphysema (91).
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OVERLAP BETWEEN ASTHMA AND COPD |
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TOPABSTRACTREMODELINGINFLAMMATIONOVERLAP BETWEEN ASTHMA AND...REFERENCES |
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CONCLUSIONS
Remodeling and inflammation occur in both asthma and COPD, but there are differences in the patterns of inflammation, the structures affected, and the prime anatomic site at which these changes occur. The differences are most apparent when nonsmoking patients with asthma and smokers with COPD from polar ends of the spectrum of reversibility are compared. It is likely that smoking influences these differences and the responsiveness to corticosteroid therapy (94). As disease becomes severe and the use of corticosteroids increases, the patterns of inflammation become more similar, mainly because of increases of neutrophils in both asthma and COPD. The increase of eosinophils and of RANTES expression in exacerbations of mild COPD further emphasizes the similarities of inflammation that can develop. Eosinophils, eosinophil chemoattractants (such as RANTES), IL-4, and mast cells may be key steroid-responsive cells and mediators in both conditions. Differential effects of steroid treatment on apoptosis may also have important, perhaps unwanted, effects (95). The effects of steroid treatment on the remodeling process, once it has been initiated, are likely to require a much longer time course than their effects on inflammation. RBM thickening (and airway smooth muscle enlargement) may be reduced only after several years of treatment (96). The predominant anatomic location and the compartmentalization of inflammatory cells to distinct tissue components may help to explain the variability in clinical expression of disease and in responsiveness to corticosteroid treatment. Recent data concerned with the nature of small-airway obstruction in COPD are now published (97). New means of delivering therapy to these distinct microanatomical target sites may advance our capacity to treat asthma and COPD. In the future, it may be more important to characterize the particular phenotype based on the predominant pattern of inflammation and remodeling than to place the patient into an either/or category of asthma or COPD.
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ACKNOWLEDGMENTS |
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The author is indebted to the many colleagues with whom he has collaborated in several of the studies cited.
(Received in original form February 17, 2004; accepted in final form July 13, 2004)
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