 1 in Asthma
Measurement in Bronchoalveolar Lavage Fluid |
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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Airway wall remodeling is an established pathological feature in asthma. Its causes are not well understood, but one mediator of potential relevance is transforming growth factor-beta 1 (TGF-
1). We
have measured levels of immunoreactive TGF-1 in bronchoalveolar lavage (BAL) fluid from clinically
stable atopic asthmatics and healthy control subjects. We have also examined the influence of allergen exposure on TGF-1 release in the airways using a segmental bronchoprovocation model, with
BAL performed at two time points following endobronchial allergen and sham saline challenges. Basal concentrations of TGF-1 were significantly higher in asthmatics than control subjects (median
8.0 versus 5.5 pg/ml, p = 0.027). Following segmental bronchoprovocation, concentrations of TGF- 1 at the allergen- and saline-challenged sites were not significantly different after 10 min, (31.3 versus 25.0 pg/ml, p = 0.78), but after 24 h there were significantly higher TGF-1 concentrations at the
allergen-challenged sites (46.0 versus 21.5 pg/ml, p = 0.017). We conclude that basal TGF-1 levels
in the airways are elevated in atopic asthma and that these levels increase further in response to allergen exposure. These findings are consistent with the hypothesis that TGF-1 is implicated in airway wall remodeling in asthma.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Epidemiological studies have established that in some forms of chronic asthma there occurs a progressive and irreversible decline in lung function (1). The cause of this process is not fully understood but one important factor is believed to be the development of structural changes (remodeling) in the airway wall (reviewed in Reference 2). Airway wall thickening in asthma was first reported in early post mortem studies of asthma fatalities. More recent morphometric studies have confirmed that the wall area is increased in both large and small airways of asthmatic subjects. This thickening involves every compartment of the airway wall, including the adventitia, submucosa, glands, and smooth muscle. In the case of the submucosa, inflammatory cell infiltration, edema, vascular congestion, and connective tissue deposition are all contributory factors. Such changes are likely to have important pathophysiological consequences as they reduce the calculated smooth muscle shortening required to cause airway closure. Mathematical modeling of airway dysfunction has revealed that the magnitude of airway wall thickening may contribute substantially to airway hyperresponsiveness which is characteristic of asthma (3).
Little is known about the mechanisms leading to these
structural alterations. In other chronic inflammatory diseases,
the generation and release of potent growth and activating
factors for fibroblasts is particularly important. Transforming
growth factor-beta (TGF-) has emerged as one of a number
of mediators which have been implicated in repair following
tissue injury. The mammalian TGF- family comprises three
isoforms denoted TGF-1, TGF-2, and TGF-3 (reviewed in
4). TGF-1 is an extremely potent stimulus to formation of
the extracellular matrix (ECM). In vitro it increases synthesis
by fibroblasts of many components of the ECM including collagen types I and III, fibronectin, vitronectin, tenascin, and proteoglycans (4). In addition, it decreases synthesis of enzymes
that degrade the ECM, such as collagenase and stromelysin,
and increases synthesis of inhibitors of these enzymes, including tissue inhibitor of metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor type-1 (PAI-1) (4).
In view of these properties, we hypothesized that TGF-1
may play a role in airway wall remodeling in asthma. To investigate this, we have made comparative measurements of basal
TGF-1 concentrations in bronchoalveolar lavage (BAL) fluid
obtained from stable atopic asthmatics and healthy nonasthmatic control subjects. To determine the influence of allergen
exposure on the release of TGF-1 in asthma, we have made
measurements in BAL fluid at two separate time points following segmental allergen or saline bronchoprovocation. We
have related these measurements to indexes of airway inflammation and remodeling.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
For measurement of basal TGF-1 concentrations, we studied a group
of 12 asthmatics (9M/3F, age 28.2 ± 2.7 yr) who were clinically stable
but had active asthma as indicated by current symptoms, prebronchodilator FEV1 measurements < 90% predicted, and airway hyperreactivity. All were using inhaled short-acting 2 agonists as required
and none had received inhaled or oral corticosteroids for at least 2 mo
before the study. One subject (number 1) was receiving treatment with
thyroxine 100 µg daily as replacement therapy. The control group
consisted of 16 subjects (4M/12F, age 22.3 ± 0.9 yr) who had never experienced symptoms suggestive of asthma and who had normal spirometry (FEV1 > 90% predicted) and airway reactivity (PC20 histamine
> 16 mg/ml). These subjects were receiving no regular medication
other than oral or injectable contraceptives. All of the asthmatics and
seven of the control subjects were atopic as defined below.
To examine the release of TGF-1 in response to allergen challenge, we performed segmental bronchoprovocation in a separate group of 12 mildly symptomatic atopic asthmatics (6M/6F, age 25.8 ± 1.5 yr) with both an allergen, to which the subject had demonstrated skin test sensitivity, and saline, as a control. Four of these subjects had
been receiving maintenance therapy with inhaled corticosteroids at
various doses but were asked to discontinue these for 48 h prior to
bronchoscopy.
All subjects were nonsmokers and none had experienced recent symptoms of upper respiratory tract infection. The clinical and physiological details of the subjects are summarized in Tables 1 and 2. The study was approved by the Southampton Joint University and Hospitals Ethical Committee and all subjects gave their written consent after being fully informed about the nature and purpose of the study.
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Atopic Status, Spirometry, and Airway Reactivity
Subjects attended for an initial screening visit during which skin prick
testing was performed, and FEV1 and airway reactivity were measured. On this occasion, asthmatic subjects were asked to discontinue
inhaled short-acting 2 agonists for a minimum of 6 h. The baseline
FEV1 was recorded using a wedge bellows spirometer (Vitalograph Ltd,
Buckingham, UK) and airway reactivity was measured as previously
described (5). Atopic status was determined by skin prick testing using the following allergen extracts: Dermatophagoides pteronyssinus,
cat allergen, mixed feathers, mixed grass pollens, and dog allergen
(Miles Inc., Hollister Stier, Elkhart, IN). A wheal response 
3 mm
diameter at 15 min to one or more of these, in the presence of negative (0.9% saline) and positive (histamine acid phosphate) controls,
was considered a positive response. In addition, 10 ml of peripheral
blood were obtained for measurement of total serum IgE (normal
range < 81 IU/ml). In those subjects who underwent segmental bronchoprovocation, the allergen used was that which produced the largest
wheal response on skin prick testing. In each case, a skin prick test
dose-response series was undertaken using serial tenfold dilutions of
allergen, and the concentration chosen for the endobronchial challenge was 1/ 10 of the lowest which produced at least a 3 mm diameter
wheal response (Table 2).
Fiberoptic Bronchoscopy, Endobronchial Allergen Challenge, and Bronchoalveolar Lavage
Fiberoptic bronchoscopy, endobronchial allergen challenge, and BAL were performed according to our previously published protocols (6, 7), conforming to current NHLBI recommendations (8). For subjects undergoing basal measurements, BAL was performed by wedging the tip of the bronchoscope into the anterior segment of the right upper lobe and instilling 6 × 20 ml aliquots of prewarmed 0.9% saline with recovery by gentle suction after each instillation. Bronchial biopsies were then obtained from proximal airway carinae. In the case of subjects undergoing segmental bronchoprovocation, the tip of the bronchoscope was first wedged into the anterior segment of the right upper lobe and 20 ml of prewarmed 0.9% saline were instilled. After 20 s the instrument was moved to the medial segment of the middle lobe and the same volume of allergen solution instilled. Excess fluid was aspirated and the two challenged segments were observed in order to confirm that bronchoconstriction occurred at the allergen-challenged site. After 10 min, BAL was performed at both sites using 120 ml 0.9% saline and the instrument was then withdrawn. Twenty-four hours later, these subjects underwent a second bronchoscopy using the same premedication as before, and BAL was again performed at both the previously challenged sites. Three subjects in this group underwent BAL 24 h after endobronchial allergen and saline instillation without a preceding 10 min lavage.
BAL Fluid Processing and Total and Differential Cell Counts
BAL fluid was passed through a 100-µm filter to remove mucus and
then centrifuged at 4° C and 600 g for 10 min to separate cells. A protease inhibitor cocktail, composed of soybean trypsin inhibitor 1 mg/
ml, 
1 antitrypsin 1 mg/ml, pepstatin A 1 mg/ml, EDTA 2.5 mg/ml,
benzamidine hydrochloride 5 mg/ml, aprotinin 1 mg/ml, and phenanthroline 0.5 mg/ml (Sigma Chemical Company, Poole, Dorset, UK),
was then added at a concentration of 1 µl per ml supernatant. Subsequently, the supernatant was concentrated 10-30 times by means of
Centriprep 3000 concentrators (Amicon, Beverly, MA) according to
the manufacturer's instructions. Centrifugation was performed at 4° C
and 1,300 g for 90, 60, 30, and 10 min, decanting and discarding the
low molecular weight fraction after each centrifugation. The concentrated supernatant was stored at 
80° C until required for analysis.
After centrifugation, the cell pellet was resuspended in phosphate-buffered saline (PBS, pH 7.4) and the total cell concentration was determined using a Neubauer improved hemocytometer (BDH, Dagenham, Essex, UK). The concentration was adjusted to 5 × 105/ml and cell preparations for differential counts were prepared by cytocentrifugation (Cytospin; Shandon Scientific Limited, Runcorn, Cheshire, UK) using 100-µl aliquots of the cell suspension per slide. These preparations were air-dried, fixed in methanol, and stained using the Hema "Gurr" rapid staining set (BDH, Lutterworth, Leicestershire, UK). Differential cell counts were performed, counting 500 cells per slide.
Quantitation of Subepithelial Fibrosis
Bronchial biopsies were fixed in acetone and embedded in glycol-methacrylate resin as previously described (9) and stored at 20° C
prior to analysis. Two-µm sections were cut using an ultramicrotome
(Om u3, C. Reichertz, Austria) and stained with toluidine blue. Photomicrographs (×1,000 magnification) of the subepithelial collagen
layer were taken only in areas where the epithelium was seen to be
clearly well orientated. Multiple measurements were made using a micrometer (Digimatic Calipers, Mitutoyo, Japan) and an average value
calculated for each biopsy.
TGF-1 Enzyme-linked Immunosorbent Assay (ELISA)
Concentrations of TGF-1 in BAL fluid concentrates were measured
using a commercially available sandwich ELISA (Predicta TGF-1 kit; Genzyme Corporation, Cambridge, MA) according to the manufacturer's instructions. Samples were activated before assay by transient acidification using 1 M HCl. The limit of detection of the assay was 50 pg/ml. All measurements were performed in duplicate. This assay is reported to show no detectable crossreactivity with TGF-2 or
TGF-3, nor with a range of other growth factors and cytokines.
Statistical Analysis
Data for age, FEV1 % predicted, and subepithelial fibrosis were expressed as mean ± SEM. Comparisons between these parameters were
undertaken using unpaired t tests. Total and differential cell counts and
TGF-1 concentrations were expressed as median (range) and PC20
values as geometric mean (range), as these measurements were not
normally distributed. Comparisons of these data were made using the
Wilcoxon test and the Mann-Whitney U test for paired and unpaired
data, respectively. Correlations were sought using the Spearman test.
A p value of < 0.05 was regarded as statistically significant. Statistical
analysis was performed using StatView 4.02 for Macintosh (Abacus
Concepts, Berkeley, CA).
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Subject Comparisons
Asthmatics and control subjects undergoing basal measurements did not differ significantly in age (28.2 ± 2.7 versus
22.3 ± 0.9 yr, p > 0.05), but FEV1 % predicted measurements
were significantly lower for the asthmatic group (83.3 ± 1.2 versus 107.7 ± 2.8%, p < 0.0001). The asthmatic subjects in
this part of the study had varying degrees of airway hyperreactivity whereas the control subjects all had PC20 values falling
outside the asthmatic range (Table 1). Asthmatic subjects in
the segmental bronchoprovocation group had milder disease
than those undergoing basal measurements only, both in
terms of their FEV1 (103.9 ± 4.8% predicted) and their airway
reactivity (PC20 histamine 2.08 [0.32 4.79] mg/ml).
Bronchoscopy Procedure
The bronchoscopy was well tolerated other than in the case of one individual in the segmental bronchoprovocation group (subject 5) who refused premedication with midazolam and who did not attend for the second bronchoscopy. In the subjects undergoing segmental bronchoprovocation, there was marked visible airway narrowing (estimated as at least 75% reduction from baseline) at the allergen- but not the saline-challenged segments, which was evident a few minutes after challenge. BAL fluid return volumes did not differ significantly between asthmatics and control subjects nor between allergen-challenged and saline-challenged segments in those subjects undergoing segmental bronchoprovocation.
Total and Differential Cell Counts
In those subjects undergoing basal measurements, eosinophil numbers were higher in the asthmatics than the control subjects, although this difference just failed to achieve statistical significance (p = 0.06) (Table 3). The two groups did not differ significantly with regard to total cell numbers or numbers of other individual leukocytes. There were no significant correlations between BAL cell counts and physiological measurements, either in the control subjects or the asthmatics. Following endobronchial allergen challenge there were significant increases in total cell numbers and in numbers of macrophages, lymphocytes, neutrophils, and eosinophils at the 24 h time point (Table 4). In contrast, only neutrophil numbers were significantly increased at this time point following endobronchial saline instillation.
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Subepithelial Fibrosis
Biopsies were unavailable or unsuitable for analysis for one of the asthmatics and five of the control subjects. In sections from the remaining biopsies, the subepithelial collagen layer could be clearly identified and was easily measured. The depth of this layer was significantly increased in the asthmatics compared with the control subjects (15.5 ± 0.6 versus 9.1 ± 0.9 µm, p < 0.0001). Collagen thickness was not significantly correlated with physiological parameters in either group. In the asthmatics there was a significant correlation between the depth of the collagen layer and neutrophil numbers (r = 0.68, p = 0.03) but not with numbers of other BAL cells.
TGF-1 Concentrations
In order to express concentrations of TGF-1 in unconcentrated BAL fluid, measured values were divided by the factor
by which the specimen was concentrated. Basal TGF-1 measurements were significantly increased in the asthmatics compared with the control subjects (8.0 [5.0-27.3] versus 5.5 [2.4-
19.7] pg/ml, p = 0.027) (Figure 1). Within the group of control
subjects, the presence or absence of atopy exerted no significant effect (p = 0.11). Levels of TGF-1 did not correlate significantly with physiological indexes or collagen measurements
in either group. In the control subjects there were significant direct correlations between TGF-1 concentrations and both total cell numbers (r = 0.53, p < 0.05) and numbers of epithelial
cells (r = 0.88, p < 0.02) in BAL fluid.
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Following segmental bronchoprovocation, concentrations
of TGF-1 at the 10 min time point did not differ significantly
between allergen- and saline-challenged segments (31.3 [9.5-
66.6] versus 25.0 [7.7-71.2] pg/ml, p = 0.78) (Figure 2). However, after 24 h there were significantly greater concentrations
at the allergen-challenged sites compared with the sham saline-challenged sites (46.0 [11.5-132.4] versus 21.5 [5.2-60.5]
pg/ml, p = 0.017) (Figure 2). Considering the data for the saline-challenged site at the 10 min time point, which are likely
to reflect basal levels in these subjects, there was no difference
between the measurements for the steroid-treated and the
non-steroid-treated subjects (p = 0.46). There were no significant correlations between BAL fluid TGF-1 concentrations at either time point and physiological or cellular parameters, other than in the case of TGF-1 values and numbers of epithelial cells at the saline-challenged site 10 min time point (r = 0.89, p < 0.03).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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In the present study, we have shown that TGF-1 is present in
BAL fluid obtained from normal individuals. This finding is in
agreement with one previous report describing measurement
of total TGF- in the epithelial lining fluid of normal subjects, although the concentrations detected in that study (approximately 5-7 ng/ml) were several hundred times greater than
those we have been able to measure (10). Even higher concentrations of TGF- (approximately 100 ng/ml) in vivo have
been reported in the lymphatic drainage from sheep lung (11).
The reasons for these differences are unclear. Nevertheless,
allowing for dilution during the lavage procedure, the levels
we have detected are within the concentration range which
would be expected to exert biological activity.
In subjects with atopic asthma, we have found that BAL
fluid TGF-1 concentrations were significantly increased in
comparison with nonasthmatic control subjects. The two groups
could also be clearly distinguished in terms of the depth of
subepithelial collagen deposition which provides an index of
airway remodeling. However, there were no significant correlations between TGF-1 concentrations and the depth of this
layer. This may reflect the fact that bronchoscopy provides
only a "snapshot" of the airway at a given moment whereas
collagen deposition is likely to reflect a summation of events
occurring over the course of weeks or months. Furthermore, in
agreement with our previous work (12), we found little spread
of these measurements within the asthmatic group. There were
also no significant correlations between basal TGF-1 levels
and numbers of leukocytes in BAL fluid, although in the case
of the control subjects there was a significant correlation with
numbers of bronchial epithelial cells. This finding may indicate increased TGF-1 release in those individuals with the
greatest epithelial fragility or damage, perhaps as part of a repair process.
To investigate the release of TGF-1 in the airways in vivo
in relation to a physiologically relevant stimulus, we have used a segmental bronchoprovocation model with measurement of
TGF-1 concentrations at two different time points. Ten minutes after exposure, there was no significant difference between concentrations at the allergen- and saline-challenged
sites. The immediate events following allergen exposure in
sensitized individuals are considered to result principally from
IgE-dependent mast cell activation. Using a similar methodology to the one employed here, previous investigators have
provided evidence for the immediate release of histamine,
tryptase, and other mast cell mediators at similar early time
points (reviewed in 13). Canine (14) and rodent (15, 16) mast
cells have been reported to synthesize TGF-1, but current
evidence suggests that production is constitutive and is not influenced by cross-linking of cell-surface IgE (16). Furthermore, production of TGF- by human mast cells has not yet been described.
In contrast to the findings at 10 min, there was a significant
increase in the BAL fluid concentration of TGF-1 at the allergen-challenged site compared with the saline-challenged site
24 h after challenge. The magnitude of this increase was variable but in only one instance was there a decrease at this time
point. This individual (number 2) was also found to have developed BAL eosinophilia at both allergen and saline-challenged sites at 24 h, perhaps indicating that some spillover of
allergen had inadvertently occurred. Increased synthesis and/
or release of TGF-1 in response to allergen exposure could occur from either resident stromal cells in the airways or from infiltrating inflammatory cells. In particular, eosinophils have been reported to represent a major source of TGF-1 mRNA
expression in both upper (17) and lower (18) airways inflammation. However, in the present study we were unable to demonstrate significant correlations between levels of TGF-1
protein and numbers of eosinophils or of other leukocytes.
Our present findings may be compared with the results of
other investigators who have examined TGF- expression in
asthma. Aubert and colleagues, using a combination of Northern analysis to detect total TGF-1 mRNA and immunohistochemistry, found no difference in expression of TGF- in
asthmatics in comparison with a control group consisting of
smokers without evidence of airflow obstruction (19). However, in that study there was heterogeneity in the origin and
processing of tissue, in the degree of disease severity and in
the treatment requirements. Furthermore, immunohistochemical staining indicated that a significant component of immunoreactive TGF-1 was extracellular and matrix-bound, perhaps suggesting there may be little direct relationship with
free TGF-1 in BAL fluid. More recently, Ohno and colleagues have examined TGF-1 mRNA expression in bronchial biopsies using in situ hybridization (18). Although these
authors found no difference between mild asthmatics and control subjects, numbers of TGF-1 mRNA+ cells were significantly increased in biopsies from patients with more severe
asthma experiencing clinical exacerbations. Taken together these findings are broadly consistent with the results of the present study.
An important factor to consider when interpreting these
results is that the ELISA protocol followed involves a transient acidification step so that total TGF-1 concentrations
are measured. TGF-1 is released from cells in a latent form
in which the mature peptide remains noncovalently associated
with the pro regions of the TGF-1 precursor. This complex
may also be bound to larger molecules known as latent TGF-1 binding proteins (20). The mechanism by which latent
TGF-1 is activated in vivo is not well understood, but is believed to involve targeting of the latent complex to the cell
surface (21) followed by the coordinate actions of a number of
cell-surface components particularly plasmin (22). As almost
all cell types examined have been found to possess cell-surface receptors for TGF-1, this activation step is believed to be
pivotal to the control of biological activity. Thus measurement
of total TGF-1 can only be considered to provide an indirect
reflection of the biological availability of the active cytokine.
In summary, our results indicate that basal concentrations
of TGF-1 in BAL fluid are increased in atopic asthma in
comparison with nonasthmatic control subjects. In addition,
allergen challenge results in the delayed release of TGF-1
into the airways of atopic asthmatics. These findings suggest
that TGF-1 release in asthma, perhaps as a result of repeated
allergen exposure, may be implicated in airway wall remodeling in this condition. Although much is now known about the
cellular inflammatory events in asthma, the mechanisms underlying chronic structural changes in the airway wall in this
condition remain relatively unexplored. Nevertheless, these
changes are potentially of great importance as they are likely
to have a profound impact on airway function. We believe that
further studies of the role of TGF-1 and other fibrogenic cytokines in asthma will prove important in defining the mediators responsible for airway wall remodeling in this condition.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. A. E. Redington, Room 4H17-21, Health Sciences Centre, Department of Pathology, McMaster University, 1200 Main Street West, Hamilton, ON, L8N 3Z5 Canada.
(Received in original form May 23, 1996 and in revised form February 27, 1997).
Acknowledgments: The authors thank Heather Brewster and Chellan Eames for technical assistance.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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