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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 1590-1595, (2002)
© 2002 American Thoracic Society

Original Article

The Relationship of Reticular Basement Membrane Thickness to Airway Wall Remodeling in Asthma

Alan L. James, Peta S. Maxwell, Gladys Pearce-Pinto, John G. Elliot and Neil G. Carroll

Department of Pulmonary Physiology, Sir Charles Gairdner Hospital, Nedlands, Western Australia

Correspondence and requests for reprints should be addressed to Dr. Alan James, Department of Pulmonary Physiology, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia 6009. E-mail: ajames{at}cygnus.uwa.edu.au


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Assessment of airway wall remodeling in asthma is difficult in vivo. The thickness of deposited extracellular matrix proteins below the epithelium, the reticular basement membrane, can be assessed by bronchial biopsy of proximal airways. The aim of this study was to determine the relationship between the thickness of the reticular basement membrane in a sample equivalent to a central airway biopsy and the dimensions of the airway wall measured on transverse sections of both central and peripheral airways. Large and small cartilaginous and membranous airways from persons who had died from asthma (fatal asthma, n = 5) or from nonrespiratory causes with asthma (nonfatal asthma, n = 5) or without asthma (control subjects, n = 5) were studied. Reticular basement membrane thickness correlated with the percentage of smooth muscle, submucosal mucous gland, and inner wall area (p < 0.05) in large cartilaginous airways, and with inner wall area and area of smooth muscle (p < 0.01) in small cartilaginous airways, but was not related to airway wall dimensions in membranous airways. These findings show that reticular basement membrane thickness of central airways, which may be assessed by endobronchial biopsy, is correlated with airway remodeling in cartilaginous airways but not with airway wall dimensions of membranous airways.

Key Words: asthma • reticular basement membrane • remodeling


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The excessive airway narrowing that occurs in patients with asthma is thought to result from airway remodeling (1), which is possibly due to airway inflammation (2, 3). Airway inflammation is long lasting, being present in subjects with asthma even during asymptomatic periods (4–6). Treatment with corticosteroids leads to a resolution of symptoms and improvements in lung function over days or weeks (7–9). Airway hyperresponsiveness (AHR) to inhaled smooth muscle agonists is observed in asthma and may be due to a combination of airway remodeling and inflammation. AHR also decreases after treatment with inhaled corticosteroids (10), although the maximum improvement may take many months (7–9). Changes in airway function and hyperresponsiveness over short periods are associated with a reduction in airway inflammation (11). This suggests that long-term improvements in AHR may be due to gradual changes in airway wall remodeling. Airway remodeling may be applied to all of the changes in the various tissue compartments associated with inflammation. In this article, remodeling refers to increased thickness of the reticular basement membrane (8, 12–17), inner and outer airway wall, the airway smooth muscle, and area of the submucosal mucous glands (1, 18). Improvements in lung function and airway responsiveness during treatment with corticosteroids are associated with reduced thickness of the reticular basement membrane in some (8) but not all (10, 13) studies. Although airway wall dimensions are changed in asthma in relationship to severity (18), the relationships between reticular basement membrane thickness (RBMt), airway wall thickness, and areas of smooth muscle and mucous glands are not known.

Airway pathology in asthma may be assessed using a number of methods. Airway inflammation may be assessed using induced sputum (19–21) and biopsy of the airway wall (2, 4, 22). RBMt, the deposition of collagen and other connective tissue proteins (stained pink on hematoxylin and eosin) below the true basement membrane, can also be measured on airway biopsies (2, 12–15, 23, 24). The assessment of other airway dimensions is more difficult, as bronchial biopsy samples a variable, superficial portion of the airway wall and crush artifact makes quantitation of airway wall components impossible. This has become important recently as measures of airway inflammation may not reflect airway function, particularly AHR (25–27). An estimate of airway dimensions from bronchial biopsy specimens might be possible, however, if RBMt, which may be assessed by bronchial biopsy, was significantly related to the dimensions of central and peripheral airways. To investigate this possibility, RBMt and airway dimensions of central airways were compared with dimensions of more distal airways in cases of fatal asthma and from cases that had died of nonrespiratory causes and either did or did not have a history of asthma.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Airways were obtained from cases coming to coroner's autopsy and were categorized as fatal asthma (n = 5), where death was caused by asthma; as nonfatal asthma (n = 5), where there was a nonrespiratory cause of death and a history of asthma was obtained; and as control subjects (n = 5), where such a history was excluded (18). Lungs were fixed in inflation with 10% paraformaldehyde at a maximum pressure of 25 cm H2O; sections (5 µm) cut from blocks of identified central airways and random parenchymal blocks were stained with hematoxylin and eosin (18). On transverse sections of cartilaginous and membranous airways, the basement membrane area and the basement membrane perimeter (Pbm), the area and perimeter defined by the outer border of the smooth muscle, the area and perimeter defined by the adventitial surface of the airway wall, the area of smooth muscle, and the area of the submucosal mucous glands were measured by using a camera lucida and digitizing tablet.

RBMt was measured in the large cartilaginous airways at x400 magnification in regions free of tissue damage (Figure 1) . A random starting point was chosen, and a single measurement was made between two points on either side of the "basement membrane," at right angles to a tangent marking the perimeter of the basement membrane at that point. For each airway, the mean of 15 measurements at 50 to 100 µm intervals from the random starting point was made. Therefore, a total length of approximately 1 mm of basement membrane was sampled, similar to that of an endobronchial biopsy. Preliminary studies showed that more than 15 measurements produced less than 5% variation in the running mean value.



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  		Figure 1. Photomicrograph (x1,000) of the wall of a large cartilaginous airway from a case of fatal asthma (stained with hematoxylin and eosin). The reticular basement membrane is a well-defined band beneath the hyperplastic epithelium. Measurements of thickness are shown as lines perpendicular to the reticular basement membrane.

 
There were one or more large cartilaginous airways available from each case; however, small cartilaginous or membranous bronchioles were not available for some cases. The inner airway wall area (defined as the difference between the area inside the basement membrane and that inside the outer border of the smooth muscle) and outer airway wall area (defined as the difference between the area inside the adventitial surface of the airway wall and that inside the basement membrane) were calculated and expressed as a percentage of relaxed airway dimensions (28). Airway smooth muscle area and gland area were expressed as a percentage of the total wall area (inner airway wall area + outer airway wall area). The percentage of smooth muscle shortening was calculated (28).

The mean dimensions of large cartilaginous (Pbm, 10–18 mm), small cartilaginous (Pbm, 4–10 mm), and membranous bronchioles (Pbm, less than 4 mm) were compared by case group using analysis of variance and post hoc, two-tailed t tests. The relationships between RBMt in large cartilaginous airways and airway dimensions in large and small cartilaginous airways and in membranous airways were assessed, with airways nested into case groups using Spearman's correlation. A probability value of less than 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects
The characteristics of the subject groups are shown in Table 1 . Asthma could be considered mild in the nonfatal group because the duration of asthma was less than the fatal group, none had used oral corticosteroids, approximately a quarter were using inhaled corticosteroids, and in most, symptoms occurred only "occasionally." None had been hospitalized because of asthma. The fatal group could be regarded as clinically severe because all had daily symptoms, some required oral corticosteroids, and most had recurrent admissions to hospital.


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  		TABLE 1. Subject characteristics

 
The sizes of airways examined, assessed by basement membrane perimeter, were similar between case groups for large cartilaginous airways, small cartilaginous airways, and membranous airways (Table 2) . Airway dimensions of large cartilaginous airways are shown in Table 3 . RBMt was significantly greater in nonfatal and fatal cases compared with control cases. There were no significant differences in other airway dimensions between control and nonfatal asthma cases. In fatal cases of asthma, the percentage of smooth muscle and the percentage of submucosal mucous glands were increased compared with control and nonfatal asthma cases. Intraobserver variation for repeat measurements of RBMt and other airway dimensions (18) was less than 5%.


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  		TABLE 2. Basement membrane perimeter (mm) in transverse sections of cartilaginous and membranous airways

 

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  		TABLE 3. Airway dimensions* in large cartilaginous airways

 
The relationships between RBMt of large cartilaginous airways and airway dimensions are summarized in Table 4 . There was no significant correlation between airway size (Pbm) and RBMt. RBMt did not correlate with airway lumen areas, outer perimeters, or outer wall areas in any airway size group. Within large cartilaginous airways, there were significant correlations between RBMt and the percentage of the inner wall area (Figure 2A) , the percentage of smooth muscle (Figure 2B), and the percentage of submucosal mucous glands. The RBMt of the small cartilaginous airways correlated with the percentage of inner wall area (Figure 3A) but not the percentage of smooth muscle (Figure 3B) in the small cartilaginous airways, although there was a significant correlation with the absolute area of smooth muscle (Table 4). RBMt was not related to areas of cartilage. The RBMt of large cartilaginous airways did not correlate significantly with any airway dimensions in membranous bronchioles (Table 4, Figures 4A and 4B) .


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  		TABLE 4. Relationship between reticular basement membrane thickness and airway wall dimensions (r values)

 



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  		Figure 2. RBMt of large cartilaginous airways versus (A) the percentage of the inner wall area (r = 0.5498, p < 0.05) and (B) the percentage of airway smooth muscle (r = 0.5069, p < 0.05) for large cartilaginous airways in control cases (circles), nonfatal asthma (triangles), and fatal asthma (squares).

 



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  		Figure 3. RBMt of large cartilaginous airways versus (A) the percentage of inner wall area (r = 0.5842, p < 0.05) and (B) the percentage of airway smooth muscle (r = 0. 2959, p < 0.05) for small cartilaginous airways in control cases (circles), nonfatal asthma (triangles), and fatal asthma (squares).

 



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  		Figure 4. RBMt of large cartilaginous airways versus (A) the percentage of inner wall area (r = 0. 1240, p > 0.05) and (B) the percentage of airway smooth muscle (r = 0.2171, p > 0.05) for membranous airways in control cases (circles), nonfatal asthma (triangles), and fatal asthma (squares).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study shows that the thickness of the RBMt in central airways is related to inner wall area, smooth muscle area, and mucous gland area in the airway wall in the same airways and to inner wall area and area of smooth muscle in smaller cartilaginous airways but not to airway dimensions in the more distal, membranous airways. RBMt was related to areas of the airway wall but not to airway perimeters or lumen area. This suggests that RBMt, measured on a bronchial biopsy from the central airways, reflects airway remodeling in central, but not peripheral, airways.

The relationship within large cartilaginous airways may have been spurious if the thickness of the basement membrane significantly contributed to and was included in the inner airway wall area. Both of these are unlikely because the RBMt, visible at x400 magnification on hematoxylin and eosin sections, contributes a small fraction (less than 5%) to the inner wall area, and measurement of the wall area involves moving a cursor along the basement membrane perimeter—usually at lower power (x40–100 magnification) so that the cursor is, on average, in the middle of the reticular basement membrane collagen layer. Cases with asthma were on various treatments. This study had too few cases to assess treatment effects. However, the confounding effects of treatment and other effects are likely to be small, as the correlations between airways were examined within subjects.

We found that using whole transverse sections of an airway only 15 measurements of RBMt over a length of approximately 1 mm, corresponding to the size of a bronchial biopsy, was necessary to obtain a stable (less than 5% variation) running mean value. Using these measurements, a difference between the fatal cases and control and nonfatal cases could be shown (Tables 2 and 3). This contrasts with the study of Sullivan and colleagues (24) using specimens obtained by endobronchial biopsy in which a much larger number of measurements were required to differentiate case groups. Case group means were used in the analyses. Because variable numbers of airways were examined in each case, the mean for a case group may be biased by increased weighting from a particular case. We therefore initially examined the data using individual airways. Using this approach, we did not observe weighting by outlying cases.

Airways only cut in transverse section were selected for measurement in this study. In airways that are not cut transversely, there is a much greater variation in RBMt. In a bronchoscopic biopsy, usually taken from airway carina, it is likely that the plane of biopsy varies greatly, and more measurements would be required to differentiate case groups (24). The range of values for RBMt found in this study was similar to those previously described for nonasthmatic control subjects and cases of mild and severe asthma (8, 12–17). On these transverse sections, there was little variation in RBMt around the airway perimeter, as values obtained by sampling the entire perimeter of the airway at random were not significantly different (data not shown). Within the groups of airways studied, we did not find a relationship between airway size (Pbm) and RBMt. Similarly, we did not observe significant relationships between RBMt in large cartilaginous airways and airway dimensions unlikely to be affected to a great extent by remodeling, such as perimeters and airway lumen (Table 4). This suggests that the relationships between airway dimensions are not due to airway size but to other processes, that is, remodeling, which affects not only RBMt but also smooth muscle area, inner wall area, and area of mucous glands, changes that occur in relationship to severity of asthma (1, 18, 29, 30). Measuring smooth muscle area on transverse section stained with hematoxylin and eosin makes it difficult to distinguish the contributions of tissue components (smooth muscle cells or extracellular matrix) to remodeling (31). However, the deposition of extracellular proteins both in the reticular basement membrane and across the airway wall is consistent with our observations.

Numerous other studies have examined the thickness of the reticular basement membrane in patients with asthma and compared them with normal individuals (8, 10, 12–16, 32). In normal subjects, the range of reported values is from 3.2 (15) to 8.4 µm (13) using light microscopy. The use of biopsy versus transverse section and electron versus light microscopy does not seem to be associated with a systematic difference (15). The effect of other factors such as tissue shrinkage and magnification has not been reported but is likely to be important. Some studies have shown a relationship to asthma severity (14), whereas others have not (12). In patients with asthma, Sont and colleagues (8) showed a significant reduction in the thickness of the RBMt after rigorously maintained treatment with inhaled corticosteroids.

The current management of asthma entails control of symptoms and achievement of best lung function. It is likely that better long-term control of symptoms will be attained using outcomes that reflect long-term changes in airway structure such as airway responsiveness (8). Thickness of the reticular basement membrane may also be an indicator of treatment efficacy/requirements in some cases. This study suggests that the reticular basement membrane reflects airway remodeling at least in central airways; however, it remains unknown whether changes in RBMt with treatment also occur in airway smooth muscle or glandular tissue.

Finally, this study shows that RBMt is not related to airway dimensions in membranous airways. Assessment of airway pathology in the peripheral airways remains an elusive goal (33). It has recently been shown that transbronchial biopsy can be used to assess peripheral airways in asthma (34), although the usefulness and safety of this approach are yet to be determined. Table 3 shows that we selected (by chance) cases of fatal asthma with less remodeling of the peripheral airways compared with the mean data of cases studied previously (18). This may have resulted in the lack of correlation between RBMt in large cartilaginous airways and the wall thickness of membranous bronchioles (Figure 4). Inclusion of fatal cases of asthma with more remodeling of the peripheral airways may have resulted in a closer correlation between central airway RBMt and peripheral airway dimensions, especially if the additional cases had a greater RBMt. Nevertheless, the cases studied still demonstrate that RBMt may be increased in the central airways; this does not necessarily predict airway wall remodeling in the peripheral airways. Further studies to address these relationships in cases with a greater range of severity of peripheral airway remodeling are required to explore this issue. The relationship between RBMt and dimensions in large airways, however, shows that measures of RBMt by biopsy or by indirect means such as optical coherence tomography (35) may provide additional information about airway pathology in asthma.


   Acknowledgments
 
Approval for this study was granted by the Ethics Committee of Sir Charles Gairdner Hospital.


   FOOTNOTES
 
Supported by National Health and Medical Research Council (NHMRC) Australia.

Received in original form August 16, 2001; accepted in final form September 26, 2002


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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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