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INTRODUCTION |
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TOP
INTRODUCTION
CONCLUSION
REFERENCES
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Despite the long-standing clinical awareness of asthma (1), knowledge of the structural basis of bronchial asthma has accumulated only relatively recently. Initial information was based on the autopsy appearances of patients dying in status asthmaticus (2) and from studies of biopsy material (3, 4). In these initial studies, the emphasis was on changes in the large airways. In autopsy material from patients dying of asthma, there was prominent mucus plugging due to the deposition of fibrin within the airway lumen, accompanied by desquamated epithelial cells, inflammatory cells, and some mucus. The changes in the wall included disruption of the epithelium with shedding epithelial cells, inflammatory cell infiltration, apparent thickening of the epithelial basement membrane subsequently shown to be due to deposition of interstitial collagen (5), hyperplasia and hypertrophy of the bronchial smooth muscle, and increase in mucus glands. Dunnill also drew attention to vasodilatation and edema of the mucosa (2).
More recent studies have documented similar changes in the large airways of patients with mild asthma (6, 7). The understanding of the pathophysiologic consequences of these changes is incomplete. An apparent relationship between the eosinophil leukocyte component of the inflammatory cell infiltrate and a score of asthma severity has been reported (8). However, such studies raise two fundamental questions; first, what is an appropriate measure of disease severity? Second, where and how should the tissue changes be quantified? By their very nature, these biopsy-based studies tend to be based on small numbers of patients, and the statistical power and interpretation of many of them is questionable.
Similarly, there are issues concerning the interpretation of immunohistochemical evidence of cellular activation, particularly of eosinophil leukocytes (9). The critical issues concerning the pathology of the small airways are whether the inflammation characteristically present in the large airways is also present in the small airways, the extent of this inflammation, and whether or not it induces structural changes. Histologic examination of autopsy material often indicates that the luminal changes of mucus plugging occur in small airways (Figure 1), which are devoid of mucus-secreting glands (10). These changes may be due to the contribution of metaplastic mucus-secreting surface endothelial cells or may represent retrograde flow or aspiration of material from the large airways. Epithelial damage is also seen, and there is a variable extent of thickening of the lamina reticularis.
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CHANGES IN THE AIRWAYS |
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Bronchiolar Walls
The clinicopathologic challenges are to correlate the age-related decline in airway function in asthma, the development of irreversible airway obstruction, and the spirometric changes induced by bronchial provocation to the morphologic appearances of the airways. Pioneering work in this regard has come from the Vancouver group (11), who have elegantly demonstrated the potential from modeling the airway behavior in asthma, based on thickening of the bronchiolar walls. Thickened bronchiolar walls exaggerate the effect of the spiraling smooth muscle on the reduction of the lumen. They may also isolate the airway from the elastic recoil of the lung, which contributes to airway patency in expiration and may thus account for the exaggerated bronchial hyperresponsiveness in asthma. These studies indicate the importance of critically evaluating the documented changes in the small airways in postmortem studies of asthma. However, these studies are fraught with technical problems. By their nature, they tend to be based on small numbers, the patients are by definition atypical, and there are no set protocols for sampling. The tissue is subject to a whole range of postmortem changes and there is no control for the effects of medication. In fact, reliable information concerning the actual usage of corticosteroids and/or other drugs may not be available.
Many of the analyses have compared changes seen in fatal asthma with the lung appearance of patients with documented asthma who have died of other causes. However, it should be noted that these asthma diagnoses may be based on information gathered by a law enforcement officer or other legal professional, who may have little knowledge or insight into respiratory disease. Thus, it is impossible to control the effect of diagnostic transfer from other obstructive airway diseases to asthma. Furthermore, review of the patients' medications does not help separate chronic bronchitis from asthma, as similar medications are used in both conditions. These limitations have been overcome in a recent detailed study of lung tissue from patients undergoing lung resection for carcinoma of the bronchus in which asthma was diagnosed on the basis of a prior physician diagnosis, more than 15% variability in airflow obstruction, and bronchial hyperresponsiveness. Patients without these characteristics were used as control subjects (12).
Inflammatory Cells
Studies have looked at the number of inflammatory cells in both the larger and smaller airways, often defining smaller airways as those less than 2 mm in diameter. Synek and colleagues evaluated leukocyte counts in the epithelium and bronchial wall of patients who had died of asthma and compared with to those from asthmatic patients who had died of other causes (13). In this study, none of the patients with bronchial asthma who died of other causes was taking three or more medications and none of these patients had received oral steroids before death. In contrast, the majority of the patients with fatal asthma had received more than three medications or oral corticosteroids. The study suggests that infiltration of the bronchial epithelium by eosinophil leukocytes is a feature of both large and small airways, with a greater intensity in the proximal airways in acute severe asthma. Similar findings have been documented in a group of five patients with sudden asphyxic asthma death, where the densities of T cells, eosinophils, and macrophages were greater in proximal airways than in airways less than 1 mm in diameter (14). Furthermore, in an evaluation of asthma deaths (15), when comparison was made in the resected lung tissue study (12) it was evident that T cell and eosinophil airway accumulation was present in both small and large airways in asthma, in comparison to well-characterized control subjects; in cases without an acute exacerbation of oral corticosteroid therapy, the presence of activated eosinophils was greatest in the smaller airways (< 2 mm). Studies of inflammatory cell infiltration thus identify the involvement of small as well as large airways in the asthma process.
Remodeling of the Airway Wall
When studies of the morphology of the airways are examined, it appears that remodeling of the airway wall occurs more consistently than inflammatory infiltrate throughout the conducting airways (16, 17). This thickening of the bronchiolar walls appears to involve both the muscular and the nonmuscular elements and occurs regardless of whether asthma caused death. Changes in airway wall thickness have been documented in airways less than 2 mm in diameter, suggesting that the entire gas-conducting component of the lung may be compromised by the tissue changes associated with asthma.
Bronchiolar Muscle Mass
The bronchiolar muscle mass shows a wide range of increases, including striking increases in individual patients, that may cause closure of the small airways and contribute to final asphyxia (Figure 2). Regression analysis of the muscle mass in airways of different sizes suggests the airway muscle is increased in fatal asthma compared with nonfatal asthma in all airways larger than 2 mm in diameter (17). Similar findings were documented by Carrol and colleagues in airways greater than 4 mm in diameter (16, 18). Computer modeling of small airway thickening, varying both airway wall thickness and the effect of pulmonary elastic recoil of the airway, reproduces the loss of plateau in the bronchial provocation dose-response curve. This model suggests that, although inflammatory cells are a smaller component of these airways, they may have a major role in determining the altered pulmonary physiology in asthma (11).
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Bronchiolar Smooth Muscle
Despite the consensus that small airway walls are thickened and their smooth muscle mass is increased, there are no data available on the function of the bronchiolar smooth muscle in asthma. This lack results from the inaccessibility of these airways and the lack of an animal model with comparable airway remodeling. Thus, all the studies indicating the functional importance of the small airways presume that the airway muscle in these small airways undergoes isotonic contraction. Although the cytoskeletal contractile elements are certainly present in these smooth muscle cells, there is no information regarding signal transduction, response to provocation, or modes of contraction (isotonic or isometric). Similarly, there is no comprehensive analysis available to help define the contribution of the individual components of the airway wall to airway resistance. The variation in the data from Carroll and colleagues (16) appears to indicate that the physiologic assumptions are not universal and that remodeling may play a disproportionate, unpredictable, and potentially fatal role in individual patients.
Taken together, these findings suggest that it is important for us to acquire a clinically applicable marker for airway remodeling. However, such a marker has not been found, and attempts at physiologic definition, imaging, and biochemical analysis of bronchoalveolar lavage fluid have all failed to clearly define evidence of tissue remodeling in the smallest airways. It is likely that there will be no single, simple marker for this process and that the algorithm analyzing small airway remodeling may have to be based on all these modalities of investigation. However, the series of studies from Carroll and colleagues led them to conclude that "biopsy of proximal airways will be representative of the inflammatory process throughout the bronchial tree in asthma" (16); although such sampling represents a different airway site, it reflects small airway events.
Collagen Deposition
A classic histologic marker of asthma, the thickening of the lamina reticularis, has been taken as evidence of airway remodeling (19). Collagen deposition beneath the basement membrane was first described as `basement membrane thickening' by Dunnill (2). More recently, this thickening has been recognized as increased collagen types III and V, together with the matrix components laminin and fibronectin deep to the true basement membrane (composed of type IV collagen) within the lamina reticularis (5). A review of different studies has shown a wide range of values for the thickness of this layer, ranging from 7 to 23 µm in patients with asthma (20). A simple point-to-point measurement between the true basement membrane and the submucosa has been shown to provide the most accurate and efficient estimate of reticular basement membrane thickness in well oriented specimens. Jeffery and colleagues have found that collagen thickness in proximal airways has been representative of its thickness in distal airways (21). Multiple factors have been associated with subepithelial collagen thickness, including frequency of asthma (22), duration of symptoms (23), T-lymphocyte activity (24), epithelial damage (5), fibroblast activity (25), and mast cell and eosinophil infiltration (26). However, the response to therapeutic intervention suggests that the extent of this thickening does not appear to relate to the severity of the disease (27); thus, it could be argued that collagen thickness is not a qualitative index of airway wall remodeling. However, more recent studies have identified a reduction in collagen deposition with corticosteroid therapy and removal from enhancing environmental factors, but with a slower response time than that previously reported for a reduction in cell accumulation and activation (28, 29). This finding suggests that these structural changes are a consequence of growth factor release associated with airway inflammation, leading to increased myofibroblast numbers and activation (25), with the net collagen thickness reflecting the balance between synthesis and breakdown. The cells associated with this fibrotic process, termed bronchial myofibroblasts, have been observed in the large airways (25) and there is also a constitutive myofibroblastic population in the human lung, termed contractile interstitial cells (30). An attempt has been made to define the relationship between these cell populations by following the anatomical compartments in resection specimens from patients with lung cancer. Our findings, although generated from a clearly atypical group of patients, indicate that there is a continuous population of subepithelial contractile cells throughout the airways and that these merge with the contractile interstitial cell network (Figure 3). The contractile interstitial cells of the lung are thought to be particularly important in regulating alveolar development, since platelet-derived, growth factor A-chain, knock-out mice lacking these cells develop emphysema (31). The contribution of bronchial myofibroblasts to the formation and remodeling of the small conducting airways is currently unknown. Because the alveolar myofibroblast population is also thought to be important in the regulation of the ventilation/perfusion matching in the airway, it may well be that the myofibroblast population in the membranous bronchioles plays a dynamic role in regulating respiratory function.
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CONCLUSION |
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TOP
INTRODUCTION
CONCLUSION
REFERENCES
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In summary, the small airways are inflamed in asthma and good data suggest that their remodeling is an important determinant of the altered airway physiology. In order to study the effects of treatment on the airway, there is a pressing need for measures of small airway function and remodeling. There are likely to be a range of changes within groups of patients. An approach combining high-resolution imaging, sophisticated flow- volume analysis, and biochemical markers may provide some basis for understanding the pathophysiology of airway obstruction in individual patients and open the possibility of designing therapies to alter the disease processes throughout the airways.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Professor William R. Roche, University Pathology, Level E, South Block, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
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References |
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INTRODUCTION
CONCLUSION
REFERENCES
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