Mast-Cell Infiltration of Airway Smooth Muscle in Asthma
Christopher E. Brightling, M.B., B.S., Peter Bradding, D.M., Fiona A. Symon, Ph.D., Stephen T. Holgate, M.D., D.Sc., Andrew J. Wardlaw, Ph.D., and Ian D. Pavord, D.M.
Background Asthma and eosinophilic bronchitis are characterizedby similar inflammatory infiltrates in the submucosa of thelower airway. However, eosinophilic bronchitis differs fromasthma in that there is no variable airflow obstruction or airwayhyperresponsiveness in the former condition. We tested the hypothesisthat there were differences between the two conditions in themicrolocalization of mast cells within the airway smooth muscle.
Methods Immunohistochemical analysis of bronchial-biopsy specimenswas completed in 17 subjects with asthma, 13 subjects with eosinophilicbronchitis, and 11 normal controls recruited from two centers.
Results Both groups with disease had a similar degree of submucosaleosinophilia and thickening of the basement membrane and laminareticularis. By contrast, the number of tryptase-positive mastcells in the bundles of airway smooth muscle from subjects withasthma (median, 5.1 mast cells per square millimeter of smoothmuscle [range, 0 to 33.3]) was substantially higher than thatin subjects with eosinophilic bronchitis (median, 0 mast cellsper square millimeter; range, 0 to 4.8) and that in normal controls(median, 0 mast cells per square millimeter [range, 0 to 6.4];P<0.001 for the comparison among the three groups). T cellsand eosinophils were not usually seen in the airway smooth musclein any of the groups.
Conclusions The infiltration of airway smooth muscle by mastcells is associated with the disordered airway function foundin asthma.
Asthma is characterized physiologically by variable airflowobstruction and airway hyperresponsiveness. Pathologically,asthma is characterized by the accumulation of eosinophils andCD4+ lymphocytes in the submucosa, mucous-gland hyperplasia,thickening of the subepithelial collagen layer, submucosal matrixdeposition, mast-cell degranulation, and hypertrophy and hyperplasiaof the airway smooth muscle.1
The extent to which airway inflammation and airway hyperresponsivenessin patients with asthma are related to one another remains controversial.2However, there is a clear dissociation between airway inflammationand airway hyperresponsiveness in patients with eosinophilicbronchitis3,4 — a condition characterized by cough thatis responsive to corticosteroids and eosinophilia detectablein sputum without variable airflow obstruction or airway hyperresponsiveness.5,6,7Since patients with eosinophilic bronchitis have higher concentrationsof histamine and prostaglandin D2 in their sputum than do patientswith asthma,7 we hypothesized that there may be differencesbetween the two conditions in the localization of mast cellswithin the airway wall. To test our hypothesis, we performeda comparative immunohistochemical analysis of bronchial-mucosa–biopsyspecimens obtained from symptomatic patients with asthma, symptomaticpatients with eosinophilic bronchitis, and normal controls.
Methods
Study Subjects
Subjects were recruited from two centers. A total of 15 subjectswith asthma, 16 subjects with eosinophilic bronchitis, and 14normal controls were recruited from Leicester, United Kingdom,and 15 subjects with asthma and 8 normal controls were recruitedfrom Southampton, United Kingdom. There was assessable airwaysmooth muscle in the biopsy specimens from 8 subjects with asthma,13 subjects with eosinophilic bronchitis, and 8 normal controlsfrom Leicester and from 9 subjects with asthma and 3 normalcontrols from Southampton (Table 1). Subjects with asthma hadcharacteristic symptoms and had variable airflow obstructionas indicated by one or more of the following: improvement bymore than 15 percent in the forced expiratory volume in onesecond (FEV1) 10 minutes after the inhalation of 200 µgof albuterol; airway hyperresponsiveness, defined by a provocativeconcentration of methacholine required to lower the FEV1 by20 percent (PC20) of less than 8 mg per milliliter; or dailyvariability of more than 20 percent in the peak expiratory flow(PEF), as measured twice daily for 14 days. Subjects with eosinophilicbronchitis had a persistent isolated cough, no symptoms suggestingvariable airflow obstruction during an observation period ofat least two months, variability of less than 20 percent inthe PEF, a normal chest radiograph, and on at least two occasionsseparated by more than two months, normal spirometric values,a PC20 for methacholine of more than 16 mg per milliliter, andeosinophilia detectable in sputum (median percentage of eosinophilsin sputum one week before bronchoscopy, 11.3 percent [range,3.5 to 68.0]). Normal subjects were asymptomatic, had no evidenceof variable airflow obstruction, and had a PC20 for methacholineof more than 16 mg per milliliter. All subjects were currentlynonsmokers with a smoking history of less than 10 pack-years.None of the subjects had taken inhaled or oral corticosteroidsfor at least six weeks before the study; all subjects with asthmaused only short-acting 2-adrenergic agonists as required. Thestudy was approved by the Leicestershire and Southampton ethicscommittees, and all subjects gave written informed consent.
Table 1. Clinical Characteristics of the Subjects.
Protocol and Clinical Measurements
The protocol required two visits one week apart. Spirometry,skin testing with allergens, and methacholine testing were performed,followed on recovery by the induction of sputum in the subjectsat the Leicester site. Spirometry was performed with a dry bellowsspirometer (Vitalograph), and the best of at least three successivereadings within 100 ml of one another was recorded as the FEV1.Skin tests were performed with Dermatophagoides pteronyssinus,cat dander, grass pollen, and Aspergillus fumigatus solutions,and normal saline and histamine were used as controls (Bencard).Subjects were considered to have a positive response to an allergenon skin testing if there was a wheal more than 2 mm larger indiameter than the negative control. The methacholine challengewas performed with the tidal-breathing method,8 with doublingconcentrations of methacholine (from 0.03 mg per milliliterto 128 mg per milliliter); aerosols were generated with a Wrightnebulizer. We extended the range of doses to include high dosesin order to explore fully the dose–response relation.Sputum was induced and processed as previously described.9
At the second visit, bronchial-mucosa–biopsy specimenswere obtained from the carinas of the right middle and lowerlobes, according to the guidelines of the British Thoracic Society10and with the use of local anesthesia and a fiberoptic bronchoscope(Olympus). All subjects received 2.5 mg of nebulized albuterol.Lidocaine (1 to 4 percent) was used for local anesthesia, andoxygen was given continuously through a nasal cannula duringthe procedure. Mucosal-biopsy specimens were immediately transferredinto ice-cooled acetone containing the protease inhibitors iodoacetamide(20 mM) and phenylmethylsulfonylfluoride (2 mM) for fixation,stored at –20°C for 24 hours, and then processed intoglycol methacrylate (Polysciences) for embedding.
Immunohistochemical Analysis
Two-micrometer sections were cut, placed in 0.2 percent ammoniasolution for one minute, and dried at room temperature for oneto four hours. The following monoclonal mouse IgG1 antibodieswere used: anti-CD3 (Dako), AA1 antibody against mast-cell tryptase(Dako), and EG2 antibody against the cleaved form of eosinophilcationic protein (Pharmacia). In a subgroup of four subjectswith asthma, additional sequential sections were stained formast-cell tryptase and chymase (Chemicon International) forcolocalization. The technique of immunostaining applied to glycolmethacrylate–embedded tissue has been described previously.11Briefly, slides were pretreated with a solution of 0.1 percentsodium azide and 0.3 percent hydrogen peroxide to inhibit endogenousperoxidase activity. After two 5-minute washes in TRIS-bufferedsaline (pH 7.6), a blocking medium consisting of Dulbecco'sminimal essential medium, 10 percent fetal-calf serum, and 1percent bovine serum albumin was applied for 30 minutes. Sectionswere then incubated with the primary antibody for 16 to 20 hoursovernight at room temperature. Bound antibodies were labeledwith biotinylated rabbit antimouse Fab fragments (Dako) duringa two-hour incubation period and detected by the streptavidin–biotin–peroxidasemethod (Dako). Aminoethylcarbazole was applied as the chromogen,resulting in a red reaction product. Sections were counterstainedwith Mayer's hematoxylin. Appropriate control sections weresimilarly treated either without the primary monoclonal antibodyor with an unrelated antibody of the same isotype (IgG1, Dako).
Assessment and Quantification
Areas of airway smooth muscle and subepithelial mucosa (laminapropria) were identified by morphologic examination, and thearea was calculated with the use of a computer analysis system(Scion). We validated our detection of airway smooth muscleby comparing the area of smooth muscle measured in 11 pairsof contiguous sections after one of each pair of sections wasassessed by morphologic examination and the other by stainingfor smooth-muscle actin (Dako). Nucleated, immunostained cellspresent in coded sections were enumerated in the lamina propriaand airway smooth muscle, and the number of cells was expressedas the number per square millimeter of submucosa and smoothmuscle. Cells were counted within the bundles of smooth musclebut not in the adjacent areas and were confirmed to be in thesubstance of the smooth muscle on the basis of serial sectionsobtained in order to avoid counting cells within the mucosaltissue that were juxtaposed owing to biopsy artifact. Tryptase-positiveand chymase-positive mast cells within the airway smooth musclewere colocalized in a subgroup of four subjects with asthmawho had sufficient airway smooth muscle. The thickness of thebasement membrane and the lamina reticularis was calculatedas the mean of 50 observations at 20-µm intervals.12
Each of two observers who were unaware of the subjects' diseasestatus examined 20 sections for the presence of airway smoothmuscle. All specimens from the three groups were intermingledduring processing and counting. A minimal area of 0.1 mm2 froma biopsy section of airway smooth muscle was considered sufficientfor the assessment of cellular infiltration, and two to foursections at least 10 µm apart were assessed for each subject;these sections came from a single biopsy in 23 subjects andfrom two biopsies in 18 subjects. There were no differencesbetween groups in the number of sections in which the area ofsmooth muscle was quantified. The area for each subject wasexpressed as the mean of the areas in all the assessable sections.In a single subject with asthma and two subjects with eosinophilicbronchitis, the basement membrane available for evaluation measuredless than 1 mm in length, so data on the thickness of the basementmembrane are not reported.
Statistical Analysis
Characteristics of the subjects are reported with the use ofdescriptive statistics. Cell counts are expressed as mediansand ranges. Data on the thickness of the basement membrane andthe lamina reticularis were normally distributed in each group,as confirmed by the Kolmogorov–Smirnov test for normality,and are reported as means ±SE. Comparisons among thethree groups were made with the Kruskal–Wallis test; theMann–Whitney U test was used for comparisons between groupsinvolving nonparametric data; and analysis of variance and unpairedt-tests were used for comparisons involving parametric data.Associations between the number of cells and the PC20 for methacholinewere established with the use of the Spearman rank-correlationmethod. The relation between the area of airway smooth muscleestimated by morphologic examination and that estimated by positivestaining for smooth-muscle actin was expressed as the intraclasscorrelation coefficient. A P value of less than 0.05 was consideredto indicate statistical significance. All tests were two-tailed.
Results
The values for submucosal eosinophil counts, mast-cell counts,and thickness of the basement membrane and lamina reticularisare presented in Figure 1. The median submucosal eosinophilcount was 2.1 per square millimeter (range, 0 to 12.4) in thenormal controls, 9.5 per square millimeter (range, 2.5 to 75.0)in subjects with asthma, and 10.0 per square millimeter (range,3.4 to 114.0) in subjects with eosinophilic bronchitis. Therewere significant differences in these counts between the controlsand both the subjects with asthma (difference, 7.4 [95 percentconfidence interval, 3.2 to 18.2]; P=0.002) and the subjectswith eosinophilic bronchitis (difference, 7.9 [95 percent confidenceinterval, 4.0 to 18.7]; P=0.002), but there was no significantdifference between the two groups with disease. There were nosignificant differences among the groups in the submucosal T-lymphocytecount (median among subjects with asthma, 48 per square millimeter[range, 22 to 122]; median among subjects with eosinophilicbronchitis, 42 per square millimeter [range, 9 to 145]; andmedian among normal controls, 53 per square millimeter [range,8 to 255]; P=0.53) or the mast-cell count (median among subjectswith asthma, 24 per square millimeter [range, 6 to 82]; medianamong subjects with eosinophilic bronchitis, 28 per square millimeter[range, 13 to 78]; and median among normal controls, 17 persquare millimeter [range, 11 to 67]; P=0.85) (Figure 1).
Figure 1. Numbers of Tryptase-Positive Submucosal Mast Cells and EG2-Antibody–Positive Submucosal Eosinophils per Square Millimeter and Thickness of the Basement Membrane and Lamina Reticularis in Subjects with Asthma, Subjects with Eosinophilic Bronchitis, and Normal Controls.
For the eosinophil count, P=0.001 by the Kruskal–Wallis test for the comparison among the three groups. For the thickness of the basement membrane and the lamina reticularis, P=0.002 by analysis of variance for the comparison among the three groups. Solid triangles represent atopic subjects, and open triangles nonatopic subjects. The horizontal lines represent the median values in the top two panels and the mean value in the bottom panel.
The mean (±SE) thickness of the basement membrane andthe lamina reticularis was significantly greater in the subjectswith asthma (10.0±0.5 µm) and those with eosinophilicbronchitis (10.8±1.4 µm) than in the normal controls(6.7±0.4 µm) (difference between subjects withasthma and normal controls, 3.3 [95 percent confidence interval,1.9 to 4.7]; P<0.001; difference between subjects with eosinophilicbronchitis and normal controls, 4.1 [95 percent confidence interval,0.9 to 7.2]; P=0.02), but there was no significant differencebetween the two groups with disease.
Smooth muscle could be readily identified by its morphologicappearance (Figure 2A). The intraclass correlation coefficientbetween the area of smooth muscle measured by morphologic examinationand that measured by positive staining for actin was 0.96. Thearea of smooth muscle assessed per biopsy section was similarin the three groups (median, 0.3 mm2 in the subjects with asthma[range, 0.16 to 0.97]; 0.35 mm2 in the subjects with eosinophilicbronchitis [range, 0.1 to 1.9]; and 0.3 mm2 in the normal controls[range, 0.12 to 0.91]; P=0.61). In the subjects with asthma,there was a median of 2 mast cells per section of airway smoothmuscle (range, 0 to 8); in the subjects with eosinophilic bronchitis,there was a median of 0 (range, 0 to 2); and in the normal controls,there was also a median of 0 (range, 0 to 5). The number ofmast cells per square millimeter of smooth muscle was significantlyhigher in the subjects with asthma (median, 5.1 [range, 0 to33.3]) than in subjects with eosinophilic bronchitis (median,0 [range, 0 to 4.8]; difference, 5.1 [95 percent confidenceinterval, 2.5 to 6.1]; P<0.001) or in normal controls (median,0 [range, 0 to 6.4]; difference, 5.1 [95 percent confidenceinterval, 0.2 to 5.9]; P=0.01) (Figure 2B and Figure 3).
Figure 2. Bronchial-Biopsy Specimens from Subjects with Asthma.
Panel A shows epithelium, submucosa, and smooth muscle with mast cells (arrows) infiltrating the airway smooth muscle (x100). Panel B shows mast cells within the airway smooth muscle (hematoxylin, x400).
Figure 3. Numbers of Tryptase-Positive Mast Cells in Airway Smooth Muscle in Normal Controls, Subjects with Asthma, and Subjects with Eosinophilic Bronchitis.
P<0.001 by the Kruskal–Wallis test for the comparison among the groups. Solid triangles represent atopic subjects, and open triangles nonatopic subjects. The horizontal lines represent the median values.
There was a significant inverse correlation between the numberof mast cells infiltrating the bronchial smooth muscle and thePC20 for methacholine in the subjects with asthma (r=–0.5,P=0.03). In a subgroup of four subjects with asthma, 83 percentof the mast cells in airway smooth muscle were positive fortryptase and chymase. Eosinophils were observed in the airwaysmooth muscle in five subjects with asthma and in two subjectswith eosinophilic bronchitis. T lymphocytes were only observedin two subjects with asthma and two normal controls. There wereno significant differences between the atopic and nonatopicpersons within a given group in terms of any of the measureswe used.
Discussion
Our results demonstrate that there is a striking differencebetween the number of mast cells in the airway smooth musclein patients with asthma and the number in both normal subjectsand patients with eosinophilic bronchitis. This observationhas potential implications for our understanding of the pathogenesisof asthma and the pathophysiological role that mast cells havein this disease.
It is possible that mast-cell infiltration of the airway smoothmuscle is a general feature of obstructive lung disease andis not specific to asthma. One limitation of our study is theabsence of a control group of subjects with other obstructivelung diseases such as chronic obstructive pulmonary disease,although given the overlap between the clinical and pathophysiologicalfeatures of asthma and chronic obstructive pulmonary disease,13such studies would have to be interpreted with careful attentionto clinical phenotype.
We used subjects with eosinophilic bronchitis as a control groupwith disease because eosinophilic bronchitis shares many ofthe features of asthma but is characterized by normal airwayfunction.4 We reasoned that any difference in pathology betweenthe two conditions would most likely be related to the featuresthat are relevant to these functional abnormalities. We observeda striking difference between the number of mast cells thatwere present in the airway smooth muscle of subjects with asthmaand the number in either normal subjects or subjects with eosinophilicbronchitis.
The hypothesis that mast cells are localized in the airway smoothmuscle and that interactions between mast cells and smooth-musclecells are important in asthma is plausible. Airway smooth musclecan provide the correct microenvironment for the differentiation,activation, and survival of mast cells.14 Several mast-cellproducts have the potential to affect adversely the growth andfunction of smooth muscle, and their microlocalization in thesmooth muscle would probably facilitate this interaction. Forexample, the mast-cell–derived autacoid mediators histamine,prostaglandin D2, and the cysteinyl leukotrienes are potentspasmogens of airway smooth muscle, and the mast-cell–specificserine protease tryptase could potentially induce bronchoconstriction,airway remodeling, and airway hyperresponsiveness through avariety of mechanisms.14,15,16,17 The hypothesis that the infiltrationof mast cells into airway smooth muscle is functionally importantis supported by our observation that the number of mast cellsin the smooth muscle of patients with asthma was inversely correlatedwith the degree of airway hyperresponsiveness.
We have previously found greater concentrations of the mast-cellproducts histamine and prostaglandin D2 in induced sputum fromsubjects with eosinophilic bronchitis than in sputum from subjectswith asthma.7 Furthermore, the number of mast cells in bronchialbrushings was significantly higher in subjects with eosinophilicbronchitis than in those with asthma.6 These observations suggestthat mast cells might preferentially localize in the superficialairway structures in patients with eosinophilic bronchitis.The assessment of airway epithelium by means of bronchial biopsiesis confounded by variation in epithelial integrity, which mayreflect a real effect of disease or an artifact18; therefore,the biopsy material collected in our study is inadequate fortesting this hypothesis. Further studies using a wider varietyof techniques to sample the lower airway are required in orderto explore in greater detail the localization of mast cellswithin the airway in patients with eosinophilic bronchitis andpatients with asthma.
Most inflammatory mediators are rapidly inactivated once theyleave the cell, so they act across distances of only a few micrometers.Microlocalization is therefore a fundamental organizing principleof inflammatory responses, although it has not been given sufficientattention in previous studies of the immunopathology of asthma— in part because thick frozen sections do not provideadequate detail for morphologic examination and only small amountsof smooth-muscle tissue can be obtained by fiberoptic bronchoscopy.With the use of glycol-methacrylate embedding and ultrathinsections, we obtained excellent samples for morphologic examination.The identification of smooth muscle was validated by means ofactin staining and was found to be reliable. Although relativelysmall amounts of smooth muscle were present, we believe ourdata are robust. There were no differences among the three groupsin the amount of smooth muscle examined, so this does not representa source of bias. The slides were studied by observers who wereunaware of the subjects' disease status, and any bias that mightresult from recognition of pathological changes caused by asthmais negated by the fact that eosinophilic bronchitis and asthmaare morphologically similar.
Our confidence in the existence of the increase we report inthe number of mast cells in airway smooth muscle in patientswith asthma is bolstered by the findings from lung-resectionand postmortem studies. Bronchial rings that exhibited contractileresponses to allergens in ex vivo studies contained more mastcells within the smooth muscle than those that were unresponsive,19and the number of mast cells within the airway smooth musclein these rings was similar to the number we found in subjectswith asthma. In patients who have died from asthma, the numberof mast cells throughout the bundles of airway smooth musclehas been reported to be higher than that in control tissue fromlung resections.20 In both these studies, mast cells were thepredominant type of inflammatory cell localized to the airwaysmooth muscle, and there was a striking paucity of eosinophilsand T lymphocytes,19,20 findings that support our suggestionthat there is a selective recruitment of mast cells.
In summary, our findings suggest that a key factor in the developmentof the variable airflow obstruction and airway hyperresponsivenessobserved in asthma is the microlocalization of mast cells withinthe bundle of airway smooth muscle; we have not ruled out thepossibility that this is a feature of obstructive lung diseasein general. Our data support the speculation that the interactionsbetween smooth muscle and infiltrating mast cells is a key elementin the development of disordered airway function in asthma.
Supported by a grant (99/004) from the National Asthma Campaign(United Kingdom). Dr. Bradding is a Wellcome Trust AdvancedFellow.
We are indebted to the subjects who participated in the study;to the Woodhouse Eaves Ladies Group for raising funds for anultramicrotome; to Dr. S. Birring, Mrs. D. Parker, and Mr. S.Barlow for technical assistance in the laboratory; and to Mrs.S. McKenna and Mrs. B. Hargadon for assistance in the clinicalcharacterization of some of the patients.
Source Information
From the Division of Respiratory Medicine, Institute for Lung Health, Leicester–Warwick Medical School and University Hospitals of Leicester, Leicester (C.E.B., P.B., F.A.S., A.J.W., I.D.P.); and the University of Southampton and Southampton General Hospital, Southampton (S.T.H.) — both in the United Kingdom.
Address reprint requests to Dr. Pavord at the Department of Respiratory Medicine, University Hospitals of Leicester, Groby Rd., Leicester LE3 9QP, United Kingdom.
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2-adrenergic agonists as required. The study was approved by the Leicestershire and Southampton ethics committees, and all subjects gave written informed consent. 
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