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(Chest. 2000;117:251S-260S.)
© 2000 American College of Chest Physicians

Comparison of the Structural and Inflammatory Features of COPD and Asthma* Giles F. Filley Lecture

Peter K. Jeffery, DSc (Med)

* From the Imperial College School of Medicine at the Royal Brompton Hospital, London, UK.

Correspondence to: Peter K. Jeffery, DSc (Med), Lung Pathology Unit, Royal Brompton Hospital, Sydney St, London, SW3 6NP, UK; e-mail: p.jeffery{at}ic.ac.uk


   Abstract
TOP
 Abstract
Introduction
 Chronic Bronchitis
 Chronic Bronchiolitis
 Emphysema
 Conclusion and Comment
 References
 
At least three conditions contribute to COPD. (1) Chronic bronchitis (mucous hypersecretion) is an inflammatory condition in which CD8+ T-lymphocytes, neutrophils, and CD68+ monocytes/macrophages predominate. The condition is defined clinically by the presence of chronic cough and recurrent increases in bronchial secretions sufficient to cause expectoration. There is enlargement of mucus-secreting glands and goblet cell hyperplasia, which can occur in the absence of airflow limitation. (2) Adult chronic bronchiolitis (small or peripheral airways disease) is an inflammatory condition of small bronchi and bronchioli in which there are predominantly CD8+ and pigmented macrophages. The functional defect is difficult to detect clinically but may be recognized by sophisticated tests of small airway function. There is mucous metaplasia, enlargement of the mass of bronchiolar smooth muscle, and loss of alveolar attachments. (3) Emphysema is an inflammatory condition of the alveoli in which T-lymphocytes, neutrophils, and pigmented alveolar macrophages are involved, associated with the release of excessive amounts of elastases. It is defined anatomically by permanent, destructive enlargement of airspaces distal to terminal bronchioli without obvious fibrosis. In contrast, asthma is a clinical syndrome characterized by allergic inflammation of bronchi and bronchioli in which CD4+ (helper) T-lymphocytes and eosinophils predominate. There is increased production and release of interleukin (IL)-4 and IL-5, which is referred to as a Th2-type response. There is usually increased tracheobronchial responsiveness to a variety of stimuli, and the condition is usually manifest as variable airflow obstruction. While differences between COPD and asthma have been highlighted, new data are emerging that indicate there may also be similarities.

Key Words: airway • asthma • biopsy • chronic bronchitis • COPD • emphysema • inflammation


   Introduction
TOP
 Abstract
 Introduction
Chronic Bronchitis
 Chronic Bronchiolitis
 Emphysema
 Conclusion and Comment
 References
 

Abbreviation: IL = interleukin

"COPD is a disorder characterized by reduced maximum expiratory flow and slow forced emptying of the lungs; features which do not change markedly over several months."1 FEV1 measurements show a more rapid, progressive deterioration with age than is normal. In patients with asthma, airflow limitation is usually, but not always, variable over short periods of time. The limitation to airflow is reversible, spontaneously or after ß-agonist inhalation, albeit an underlying irreversible component may develop in the older asthmatic or when inflammation persists in association with repeated allergen or occupational exposure. Extrinsic (allergic), intrinsic (late onset), and occupational forms are recognized. Also, of course, there may be mixtures of COPD and asthma that coexist in any one patient, and the proportion of the "mix" may be dictated by smoking habits.

The following synopsis considers the salient structural and inflammatory changes that occur in patients with chronic bronchitis, chronic bronchiolitis, and emphysema.


   Chronic Bronchitis
TOP
 Abstract
 Introduction
 Chronic Bronchitis
Chronic Bronchiolitis
 Emphysema
 Conclusion and Comment
 References
 
Structural Changes
In bronchial biopsy specimens taken from patients with mild airflow obstruction, there is fragility, damage, and variable loss of surface epithelial cells even in patients with mild stable asthma: the extent of such loss shows a negative correlation with airways hyperresponsiveness2 3 4 (Fig 1 , top). Epithelial integrity has not yet been extensively studied in patients with stable chronic bronchitis and COPD, but there are reports of minimal loss.5 In contrast to patients with asthma, the epithelium in those with chronic bronchitis is normally intact and shows a squamous metaplastic change (Fig 1 , bottom) or goblet cell hyperplasia. The bronchial biopsy specimens of patients with chronic bronchitis and of those with COPD have a reticular basement membrane thickness that is within the normal range.6 In patients with asthma, the uniform thickening of the reticular layer of the epithelial basement membrane and its hyaline appearance are key features that are usually associated with a tissue (and blood) eosinophilia (Fig 1 , top). When compared to patients with COPD, the difference in thickness of the reticular basement membrane remains for age-matched and disease severity-matched asthmatics even when they are being treated with inhaled corticosteroids (Table 1 ). However, Chanez and colleagues7 have demonstrated in a subset of patients that smokers who show a significant reversibility following 14 days of oral prednisolone therapy, but who were clinically defined as having COPD by their lack of reversibility to inhaled ß-agonists, have a thicker reticular basement membrane than is normal and that this condition is associated with BAL eosinophilia. The structural and inflammatory profile seen in the bronchial biopsy specimens of this subset of COPD patients renders the distinction between asthma and COPD less clear.



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  		Figure 1. Figure 1 . Bronchial biopsy specimens of the airway mucosa. Top: a subject with mild allergic asthma showing the loss of surface epithelium and the homogeneous thickening of the reticular basement membrane. Bottom: a heavy smoker (FEV1, 40% of predicted) demonstrating an intact epithelium that has undergone squamous metaplasia. By contrast, the reticular basement membrane is relatively thin (alkaline phosphatase antialkaline phosphatase, original x240).

 

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  		Table 1. Changes in Inflammatory Cells: Comparison of Smokers With Chronic Bronchitis, COPD, and Asthma vs Their Respective Healthy Control Subjects*

 
Cough and sputum production are the symptoms most frequently experienced by smokers, but these also often occur in patients with other conditions, including asthma; these mechanisms are effective in clearing proximal airways down to about the sixth generation of branching. Tracheobronchial hyperplasia of goblet cells and mucous gland enlargement are histologic features of chronic bronchitis that also occur, to a similar degree, in asthma.8 The enlargement of the bronchial gland mass in patients with COPD has been reported as a histologic hallmark of chronic bronchitis. However, there appears to be a unimodal distribution of gland size between normal subjects and patients with bronchitis, and, interestingly, the extent of inflammation shows a better correlation with sputum volume than does gland size.9 There is a disproportionate reduction of serous acini of the submucosal glands, which contain lysozyme, lactoferrin, and an antiprotease of small molecular weight. This favors bacterial colonization and proteolysis, and there is a report that this situation does not occur in patients with asthma.10 Other epithelial changes in patients with chronic bronchitis and COPD at the end stage of the disease may include atrophy,11 focal squamous metaplasia,12 ciliary abnormalities,13 and decreases of both ciliated cell number and mean ciliary length.14 15 16 There is mucous plugging of the airways in patients with both COPD and asthma, but the airways in patients with fatal occurrences of asthma are occluded by plugs of exudate and mucus. The mixture of inflammatory cells, sloughed epithelial cells, and mucus is a particularly tenacious secretion that is extremely difficult to remove by cough.17 18 Additionally, in patients with asthma, bronchial vessel dilatation, congestion, and edema are features that may contribute to swelling of the mucosa, an alteration that may be particularly important in occurrences of exercise-induced asthma.

Marked enlargement of bronchial smooth muscle mass is another characteristic feature of large and medium-sized airways of the severe asthmatic, a change that is particularly prominent in those who die of their asthma (Fig 2 ).17 19 An increased total amount of airway smooth muscle also occurs in patients with COPD, but this is most striking in small bronchi and bronchioli.20 Whether proliferation, hypertrophy, or altered states of differentiation are responsible for this change is unclear. There is recent interest in the bronchial myofibroblast or fibromyocyte as the origin of the enlarged muscle mass in patients with asthma. While this cell phenotype has been thought previously to differentiate from an existing population of fibroblasts, it is now likely that the dedifferentiation of existing smooth muscle and its migration to a subepithelial site occurs.21 The latter process may parallel the changes to vascular smooth muscle described in patients with atherosclerosis.22



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  		Figure 2. Figure 2 . Scanning electron microscopy of the wall from a patient with fatal case of asthma showing two major factors that contribute to airway wall thickening: (1) dilatation and congestion of bronchial vessels (V); and (2) enlargement of the blocks of bronchial smooth muscle (SM) (original x120).

 
Inflammation
The bronchial mucosa of smokers has been the focus of recent biopsy studies using flexible fiberoptic bronchoscopy. These biopsy studies are of particular interest as they allow comparison with the numerous biopsy studies reported previously in patients with asthma.

It is already recognized that in both atopic (extrinsic) and nonatopic (intrinsic) asthma that there is an inflammatory infiltrate comprised of activated (CD25+) T-helper (CD4+) lymphocytes and activated (EG2+) eosinophils associated with gene expression and secretion of interleukin (IL)-4, IL-5, IL-10, IL-13, and the proinflammatory cytokines granulocyte macrophage colony-stimulating factor and tumor necrosis factor {alpha}.2 23 24 25 26 27 28 The production of IL-4 and IL-5, but not IL-2 and interferon {gamma}, is referred to as the Th2 phenotype and is considered to be a characteristic cytokine profile of allergic inflammation. In bronchial biopsy specimens of subjects with stable COPD and exacerbations of bronchitis, there is now ample evidence of an inflammatory cell infiltrate5 29 30 31 32 associated with up-regulation of cell-surface adhesion molecules31 32 (Fig 3 , top). Bronchial mononuclear cells appear to form a predominant cell type with scanty neutrophils (in the absence of an exacerbation of infection): the mononuclear component comprises lymphocytes, plasma cells, and macrophages. Significant increases are reported in the numbers of CD45 (total leukocytes), CD3 (T-lymphocytes), CD25-activated, and VLA-1+ (late activation) cells and of macrophages.30 The results of the biopsy study by O’Shaughnessy and coworkers33 demonstrate that in smokers with COPD T-lymphocytes and neutrophils increase in the surface epithelium, as do T-lymphocytes and macrophages in the subepithelium. In COPD, it is the CD8+ (cytotoxic/suppressor) lymphocyte (not the CD4+ T-cell subset) that increases in number and proportion to become the predominant T-cell subset (Fig 3 , center and bottom). The increase of CD8+ cells shows a negative association with decline in lung function33 (Fig 4 ). The increase of the CD8 phenotype and of the CD8/CD4 ratio occurs in both the mucosa and submucosa, which is associated with mucus-secreting glands.33 34 These findings contrast with the predominance and activation of the CD4+ T-cell subset, the characteristic T-cell subset of mild atopic asthma.



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  		Figure 3. Figure 3 . A bronchial biopsy specimen from a smoker with chronic bronchitis from which three adjacent tissue sections have been cut and immunostained to demonstrate three distinct inflammatory cell phenotypes. Top: leukocytes that are CD45+. Center: leukocytes that are CD8+ (ie, suppressor/cytotoxic). Bottom: leukocytes that are CD4+ (T-helper cells). In contrast to asthma, the predominant T-cell in COPD is the CD8 phenotype (alkaline phosphatase antialkaline phosphatase original x60).

 


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  		Figure 4. Figure 4 . Plot showing the association between the number of CD8+ cells and FEV1 percent predicted in large airways: the more CD8+ cells, the lower the FEV1 percent predicted. Reprinted with permission from O’Shaughnessy et al.33

 
There is a small, but significantly increased, number of tissue eosinophils compared to that found in healthy control subjects, and it has been suggested that, in contrast to patients with asthma, the tissue eosinophils found in those with COPD do not degranulate.29 However, the numbers of tissue eosinophils are markedly and significantly increased when there is an exacerbation of bronchitis, which is defined as a need by the patient to seek medical attention due to a sudden worsening of dyspnea or an increase in sputum volume or purulence.32 35 Interestingly, the increase of eosinophils in exacerbations of bronchitis is reported not to be accompanied by increases in the number of inflammatory cells showing immunoreactivity for IL-5 protein.36 As IL-5 seems to be a key molecule in inducing the terminal differentiation and release of eosinophils from bone marrow, its absence in these patients is unexpected. However, we have recently found37 that airways resected from the lungs of nonasthmatic smokers demonstrate marked gene expression for both IL-4 and IL-5, and this is especially associated with the bronchial glands of subjects with chronic hypersecretion. Thus, IL-5 in patients with chronic bronchitis could be synthesized and secreted on demand without the intracellular storage of the molecule that allows its identification by immunostaining.

Sputum eosinophilia also are reported in cases of "eosinophilic bronchitis," ie, in patients without a history of asthma and without bronchial hyperresponsiveness.38 These cases of eosinophilic bronchitis question the role of eosinophils in asthma, and the airway mucosa will need to be examined for evidence of early asthmatic changes. These observations, and those cited earlier, bring into question the putative definitive distinctions between chronic bronchitis and asthma and present us with a new challenge for further research.

It is interesting that the high number of neutrophils found in BAL fluid from subjects with COPD39 is not seen in the bronchial mucosa, at least in the subepithelial zone, the area of the biopsy that usually is quantified.33 40 The studies by O’Shaughnessy and coworkers41 and Saetta and colleagues34 demonstrate the close relationship of neutrophils with surface epithelium (Fig 5 ) and mucus-secreting glands, respectively. The reasons and consequences of the compartmentalization of distinct inflammatory cells in the airway mucosa will need to be considered in the future.



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  		Figure 5. Figure 5 . A bronchial biopsy specimen from a smoker with chronic bronchitis, stained for neutrophil elastase, illustrating the regional distribution and accumulation of neutrophils in the surface epithelium (alkaline phosphatase antialkaline phosphatase, original x60).

 

   Chronic Bronchiolitis
TOP
 Abstract
 Introduction
 Chronic Bronchitis
 Chronic Bronchiolitis
Emphysema
 Conclusion and Comment
 References
 
Structural Changes
The small airway defect in patients with COPD is characterized by persistent airflow limitation, which may show progressive deterioration in the absence of emphysema. While the site of the lesion and its detection in patients with COPD is, as yet, difficult to pinpoint by tests of lung function, experimental physiologists (inter alia42 43 ) have indicated that the dominant site lies in small bronchi and bronchioli of < 3 mm diameter.

The measurement of sputum only reflects secretions obtained by cough from about the first six generations of airway branching. Mucus produced at this proximal site both in patients with COPD and those with asthma likely serves to protect the more distal and respiratory portions of the lung. However, in patients with COPD, mucus produced inappropriately in bronchioli by the process of mucous metaplasia44 45 has a number of detrimental effects, including a reduction of bronchiolar antiproteases, leading to bronchocentric proteolytic digestion and the development of centrilobular emphysema in smokers with COPD. In bronchioli, goblet cells are absent or sparse and nonciliated secretory and ciliated cells are the main cell types.46 47 Of these cell types, the Clara cell is the major secretory phenotype as well as the progenitor from which ciliated and newly formed mucous cells develop. It has been suggested that Clara cells normally produce both a hypophase component of bronchiolar surfactant and a low-molecular-weight protease inhibitor (ie, antileukoprotease or bronchial mucosal protease inhibitor). The latter is the main antielastase screen in sputum and normally prevents autolysis of airway tissues.48 In smokers, Clara cells are replaced by mucous cells,45 and mucus appears in peripheral airways, with its secretion abnormally increased therein.49 The increase in mucus at this distal site is, therefore, difficult to clear by cough. In addition, the replacement of the normal surfactant lining by mucus leads to an abnormally high surface tension and small airway instability, and predisposes it to early airway closure during expiration.50 Whether mucous metaplasia occurs in patients with asthma is still debated: there is some evidence for it and for goblet cell secretion, which remains unusually adherent to the mixture of exudate and mucus that forms the luminal plug.51 The alternative in patients with asthma is that the secretions seen in bronchioli have been aspirated from larger airways and are not produced locally.

Other key structural changes in patients with COPD include the following: bronchiolar smooth muscle hypertrophy; mural edema; peribronchiolar fibrosis; and an excess number of airways that are < 400 µm in diameter.44 52 53 54 The resultant stenotic narrowing of bronchioli has been convincingly demonstrated by Bignon and colleagues.55 The peribronchiolar inflammation (Fig 6 , top) and fibrosis may contribute to the development of centrilobular emphysema and may be responsible for the subtle abnormalities detected by lung function tests in patients with COPD. An associated loss of alveolar attachments to the airway perimeter (Fig 6 , bottom) contributes to the loss of elastic recoil and favors increased tortuosity and early closure of bronchioli during expiration in patients with COPD.56 57 58 Thickening of the reticular basement membrane and smooth muscle mass enlargement and airway plugging also occur in bronchioli in patients with asthma. However, the loss of alveolar attachments is not reported in patients with asthma in the absence of a history of smoking.



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  		Figure 6. Figure 6 . Small airways disease demonstrated in bronchial sections. Top: a transverse section of a small airway with peribronchiolitis consisting predominantly of lymphocytes (hematoxylin-eosin, orginial x45). Bottom: loss of alveolar attachments and collapse of the airway (hematoxylin-eosin, orginial x12).

 
Inflammation
It is suggested that the primary lesion is persistent and progressive inflammation, which then leads to peribronchiolar fibrosis. Histologically, one of the most consistently observed early effects of cigarette smoke in patients with COPD is a marked increase in the number of macrophages and neutrophils in the airways of humans and in those studied in experimental animal models of this condition. This represents a respiratory bronchiolitis and alveolitis consisting of pigmented macrophages,59 cells that also can be detected by BAL.44 52 60 There are studies that examine the peribronchiolar inflammation of smokers whose lungs had been resected for localized tumor. By comparison with smokers who do not have those symptoms, those with chronic bronchitis and COPD have increased numbers of CD8+ cells.20 61 As with the CD8+ T-cell predominance in the large airways, these inflammatory changes to small airways appear also to be related to clinical airflow obstruction in COPD, and the negative association with FEV1 appears to be stronger than that seen in the bronchi42 62 63 (Fig 7 ). Interestingly, the results of studies of tissue that has been resected from asthmatic smokers whose lungs have been removed due to localized tumors also demonstrate the involvement of small airways in asthmatics who smoke. As with nonsmoking asthmatics, there is marked tissue eosinophilia and increased gene expression for IL-5.64



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  		Figure 7. Figure 7 . Demonstration of the association between the number of CD8+ cells and FEV1 percent predicted in small airways: the negative correlation previously shown in large airways is even stronger in small airways, which are considered to be the major site of airflow obstruction. Reprinted with permission from Saetta.20

 

   Emphysema
TOP
 Abstract
 Introduction
 Chronic Bronchitis
 Chronic Bronchiolitis
 Emphysema
Conclusion and Comment
 References
 
Structural Changes
The early changes of emphysema have been thought to include subtle disruption to elastic fibers with an accompanying loss of elastic recoil, bronchiolar and alveolar distortion, and the appearance of fenestrae that enlarge,65 66 an alteration that has been referred to as microscopic emphysema (Fig 8 , top and bottom). These biochemical and microscopic changes subsequently lead to the loss, by destruction of the elastic framework, of the interalveolar septa and to the appearance of spaces, > 1 mm in diameter, which can be detected macroscopically (Fig 9 ). Recent data have shown that this destructive process is accompanied by a net increase in the mass of collagen: this suggests that, contrary to the current internationally accepted definition (see earlier), there is alveolar wall fibrosis even in otherwise emphysematous lungs.67 While emphysema and right ventricular hypertrophy are common in patients with COPD, both are uncommon in those with asthma. In patients with asthma there is also controversy as to whether there is loss of elastic tissue.68 69



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  		Figure 8. Figure 8 . Alveolar walls. Top: scanning electron microscopy of alveoli from the lung of a nonsmoker showing many alveoli with only the occasional "pore of Kohn": these pores allow for collateral ventilation (arrows) (original x50). Bottom: scanning electron microscopy showing microscopic emphysema, which begins as fenestrae that enlarge to give the alveoli a ragged appearance and probably are associated with a loss of elastic recoil. These changes would be too small to see with the naked eye (original x100).

 


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  		Figure 9. Figure 9 . Gross appearance of a slice through a lung in which there is centrilobular emphysema demonstrating the destruction of the lung predominantly in the upper aspects of each lobe (original x0.3). Image courtesy of Professor B. Heard.

 
Inflammation
The destruction of the respiratory zone in patients with emphysema also is considered to be the result of an inflammatory reaction, much of this centered on respiratory bronchioli and the alveolar wall. The working hypothesis has been that emphysema is the result of an imbalance between proteolytic enzymes and protease inhibitors in the lung, favoring an excess of enzymes and, in particular, elastases: lung connective tissue, primarily elastin, undergoes repeated destruction, synthesis, and degradation.70

In addition, the imbalance between oxidants and antioxidants contributes to the protease-antiprotease imbalance by allowing an excessive oxidant burden to degrade the normal protease inhibitor screen.71 72 Tobacco smoke recruits neutrophils to the lung,72 73 74 and the proposed mechanism involves interactions between cigarette smoke, alveolar macrophages, chemoattractants, neutrophils, elastases, endogenous and exogenous oxidants, protease inhibitors, and antioxidants. Traditionally, the source of elastase has been considered to be the serine elastases of the neutrophil, but there are cysteine and metalloproteinase families that also have been identified in inflammatory and resident lung cells.75 The recent use of gene-targeted (knock-out) mice has demonstrated the importance of macrophage metalloelastases in the induction of cigarette smoke-induced emphysema.76

Lymphocytes also have been demonstrated to form a significant component of the alveolar wall inflammatory infiltrate in COPD.77 The greater the number of T-lymphocytes, the less alveolar tissue is present (Fig 10 ). Controversially, the same authors found that the more neutrophils there were, the more tissue was present, which would appear not to support the above "neutrophil hypothesis" and conflicts with the results of morphometric analyses of emphysematous lung reported by Hogg and colleagues.42 In asthma, inflammatory changes in the region of alveolar attachments to bronchiolar walls also are reported by examination of transbronchial biopsy specimens. Kraft and colleagues78 have demonstrated an increase in alveolar wall eosinophils in patients with nocturnal asthma: there were more alveolar wall eosinophils at 4:00 AM than at 4:00 PM, and the alveolar tissue eosinophilia correlated with decreased lung function at the earlier time point. The pathologic significance of this bronchocentric alveolar inflammatory infiltrate in asthma needs to be determined.



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  		Figure 10. Figure 10 . A graph showing the negative relationship between the number of T-lymphocytes and an index of tissue destruction: the more T-lymphocytes present in the alveolar region, the less tissue is present. Adapted from Finkelstein.77

 

   Conclusion and Comment
TOP
 Abstract
 Introduction
 Chronic Bronchitis
 Chronic Bronchiolitis
 Emphysema
 Conclusion and Comment
References
 
There is evidence of inflammation in both COPD and asthma, but there are marked differences in terms of the predominant phenotype and the anatomic/mucosal site and in the functional consequences of such inflammation. Inflammation appears to be present throughout the bronchial tree and in the respiratory portion of the lung in patients with COPD. There is inflammation of bronchi and bronchioli in patients with asthma and even eosinophilia of the alveolar/bronchiolar attachment zone. The involvement of activated lymphocytes seems to be a common theme in both conditions, yet the profound tissue eosinophilia of patients with stable asthma does not appear in those with COPD until there is an exacerbation. Accordingly, the predominant lymphocyte subsets in COPD and asthma appear to be distinct, ie, CD8+ vs CD4+ cells, respectively. There is a need to understand the cytokines produced by the CD8+ T-cells in COPD as T-cytotoxic (TC2-type) cells have now been identified that, like Th2-type cells have the capacity to produce IL-4 and IL-5.

Understanding the functional consequences of persistent inflammation and the ensuing structural damage/remodeling of airway and lung structures in patients with COPD and asthma is important. The mucus hypersecretion that characterizes chronic bronchitis traditionally has been considered to be irrelevant to the accelerated rate of decline in FEV1 and to the disability of COPD.79 80 However, even the role of this apparently innocuous feature of chronic bronchitis has recently been questioned again, as two relatively recent studies demonstrate that sputum volume is associated with accelerated decline in FEV1, increased numbers of hospital admissions, and increased mortality.81 82 This is in addition to the undoubted detrimental effects of mucus on the stability of small airways in COPD.50 While there is consequent tissue destruction and remodeling in the periphery in COPD, there seems to be a contrasting trend toward involvement of relatively large proximal airways in asthma, particularly with respect to the early thickening of the reticular basement membrane and, in fatal cases of asthma, enlargement of the mass of bronchial smooth muscle, which are changes that have been thought not to occur in the large airways in COPD. The tissue distinctions between COPD and asthma are by no means always clear. Two studies indicate that oral prednisolone administration uncovers a subgroup of patients with COPD who show a degree of airways reversibility associated with histologic features of asthma,7 and there are patients with sputum eosinophilia who do not show the characteristic clinical features of asthma. The number of smokers with the combined structural and inflammatory features of both COPD and asthma are likely to be more frequent than we currently appreciate from the currently reported studies that compare the highly selected groups of smokers with mild COPD and nonsmokers with asthma.

Finally, because many lifelong smokers do not succumb to emphysema, constitutional factors are likely to be of importance also. A genetic deficiency of {alpha}1-antitrypsin is well documented, and smoking in this group clearly advances the onset of emphysema and accelerates its subsequent progression. Other genetic factors, such as variation in cellular response to cytotoxicity, phagocytosis, enzyme release by both neutrophils and macrophages, and cytokine polymorphisms such as those recently reported for tumor necrosis factor {alpha} may be important determinants of susceptibility to cigarette smoke.85 More recently, O’Shaughnessy and colleagues33 suggest that airway (and lung) susceptibility to the effects of cigarette smoke will likely be greater in those individuals who already have a genetically determined low CD4/CD8+ cell ratio in their peripheral blood,86 which occurs in about 5% of the population and is a novel explanation as to why only a proportion (about 20%) of smokers succumb to the deleterious effects of smoking on the lung. These hypotheses now require testing by further immunopathologic, molecular, and epidemiologic research.


   Acknowledgements
 
I thank Mr. Andrew Rogers for his valuable assistance with the illustrations.


   References
TOP
 Abstract
 Introduction
 Chronic Bronchitis
 Chronic Bronchiolitis
 Emphysema
 Conclusion and Comment
 References
 

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