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(Chest. 2002;122:1553-1559.)
© 2002 American College of Chest Physicians

Matrix Metalloproteinase-9, but Not Tissue Inhibitor of Matrix Metalloproteinase-1, Increases in the Sputum From Allergic Asthmatic Patients After Allergen Challenge*

Didier D. Cataldo, MD, PhD{dagger}; Jane Bettiol, MD, PhD{dagger}; Agnes Noël, PhD; Pierre Bartsch, MD; Jean-Michel Foidart, MD, PhD and Renaud Louis, MD, PhD

* From the Departments of Pneumology (Drs. Cataldo, Bettiol, Bartsch, and Louis) and Biology of Tumor and Development (Drs. Noël and Foidart), University of Liège, Liège, Belgium.

Correspondence to: Didier Cataldo, MD, PhD, Department of Pneumology, CHU Sart-Tilman, 4000 Liège, Belgium; e-mail: Didier.Cataldo{at}ulg.ac.be


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: The aim of the study was to determine whether allergen inhalation modulates the levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 in the induced sputum recovered from patients during a late-phase reaction.

Method: Eight allergic asthma patients and five healthy control subjects inhaled a dose of Dermatophagoides pteronyssinus extract corresponding to the provocative concentration of the allergen causing a 20% fall in FEV1 and saline solution. Lung function was carefully monitored for 6 h, and an induced sputum test was performed at 6 h after sham challenge or allergen challenge. The total and differential cell counts were analyzed, and the levels of MMP-9 (by enzyme-linked immunosorbent assay [ELISA] and zymography), TIMP-1 (by ELISA), and albumin (by rocket immunoelectrophoresis) were measured.

Results: The sputum eosinophil counts (p < 0.01) and MMP-9 levels (p < 0.05) increased significantly in atopic asthma patients after undergoing the allergen challenge but did not in the control subjects. By contrast, TIMP-1 and albumin levels were not significantly increased in any group. MMP-9 levels, measured after the allergen challenge in asthmatic patients, were significantly correlated with FEV1 variations after allergen inhalation (r = 0.51; p < 0.05) and with the sputum neutrophil percentage (r = 0.71; p < 0.01).

Conclusion: The levels of MMP-9, but not TIMP-1, increase after inhaled allergen challenge in the sputum of allergic asthmatic patients. This protease increase may lead to a transient imbalance between MMP-9 and TIMP-1 favoring proteolytic extracellular matrix degradation.

Key Words: allergen bronchial provocation test • asthma • matrix metalloproteinases-9


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Matrix metalloproteinases (MMPs) are a family of calcium-dependent and zinc-dependent enzymes secreted from cells as inactive zymogens. Members of the MMP family are selectively inhibited by the tissue inhibitors of matrix metalloproteinases (TIMPs).

Asthma is a chronic inflammatory disease of the airway leading to a progressive loss of lung function.1 The changes in the physiologic properties of the airway in asthma patients is thought to be caused by a bronchial remodeling2 that is induced by repeated acute inflammation associated with allergen exposure.3 However, it is still unknown how the allergic airway inflammation is related to the process of airway remodeling. There are several arguments to suggest that MMPs are implicated in this process. First, MMP-9 has been found in increased levels in both BAL fluid and sputum from asthmatic patients and was correlated to the extent of the inflammatory cells infiltrates.4 5 6 Increases in MMP-9 messenger RNA and proteins also were detected in the bronchial walls of asthmatic patients.7 8 Moreover, it was reported that a segmental allergen challenge induces an increase in MMP-9 and its physiologic inhibitor, TIMP-1,9 and that MMP-9 is increased and activated in the BAL of patients with status asthmaticus.10 Second, it has been reported that the inhibition or the lack of MMPs, and in particular a lack of MMP-9, prevents the occurrence of an asthmatic phenotype in a mouse model of asthma.11 12 MMP-2 also could be implicated in the bronchial remodeling since it is required for smooth muscle proliferation in vitro13 and was described as being present in the sputum of asthmatic patients.4 The purpose of the present study was to determine whether the exposure to an inhaled allergen induces any change in MMP-9 and TIMP-1 secretion in the airways of asthmatic patients. Allergen challenges were performed by nebulization in eight allergic asthmatic patients and five healthy control subjects, sputum was induced 6 h after the challenge, and the results were compared with those obtained after a sham challenge.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Design of the Study
The study consisted of four visits 1 week apart. The first visit consisted of a clinical examination, skin-prick tests, a lung function test, and a methacholine challenge. The second visit was devoted to a sham challenge consisting of the inhalation of isotonic saline solution for 5 min, monitoring of lung function, and an induced sputum test performed 6 h after the inhalation of the saline solution. The third visit was devoted to an allergen challenge to determine the provocative concentration of a substance (the allergen) causing a 20% fall in FEV1 (PC20). The fourth visit consisted of an allergen challenge, using a single dose of the allergen concentration corresponding to the PC20 for the allergen, which was inhaled during a 5-min nebulization. Lung function was monitored for 6 h, and sputum induction was performed by the sixth hour.

Subjects
Eight allergic asthmatic patients and five healthy control subjects were studied (Table 1 ). The patients were classified as having asthma using the criteria of the American Thoracic Society.14 All asthmatic subjects displayed skin-prick test results that were positive for Dermatophagoides pteronyssinus, had increased levels of total IgE, had clinical histories of perennial asthma symptoms, and a methacholine PC20 of < 4 mg/mL. The subjects included in the control group were healthy, had skin-prick test results that were negative for common aeroallergens, and had low total IgE levels. None of the subjects included in this study had experienced any bronchial infections or exacerbations of asthma during the 6 weeks preceding the study. All subjects gave their written informed consent, and the protocol of the study was approved by the ethical committee of our hospital.


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  		Table 1.. Patient Characteristics*

 
Assessment of Bronchial Reactivity to Inhaled Allergen
In order to determine the individual bronchial responsiveness to the allergen, a challenge was conducted with a D pteronyssinus extract (Stallergen; Antony, France) diluted in an isotonic saline solution that had a reactivity index ranging from 0.2 to 5. The PC20 of the allergen was calculated from a cumulative dose-response curve, as described previously.15 All healthy subjects received a cumulative concentration of D pteronyssinus with a reactivity index of 6.

Sputum: Induction and Processing
Sputum induction was performed by inhalation of hypertonic saline solution (NaCl, 4.5%) after premedication with inhaled salbutamol, 400 µg, as described previously.4 The collected sputum was diluted fivefold in phosphate-buffered saline solution in order to homogenize the suspension, and, after centrifugation, the supernatants were snap-frozen in liquid nitrogen and stored at -80°C in order to avoid the activation or degradation of MMPs by other proteolytic enzymes.

Measurement of MMP-9, TIMP-1, and Albumin
Gelatin zymography was performed as previously described.4 MMP-9 and TIMP-1 were measured using commercially available enzyme-linked immunosorbent assay (ELISA) [Quantikine human MMP-9 immunoassay and Quantikine human TIMP-1 immunoassay; R&D Systems; Minneapolis, MN]. The MMP-9 ELISA measured both active and pro-MMP-9. Albumin levels were measured in the supernatant of induced sputum by rocket immunoelectrophoresis as previously described.16

Statistical Analysis
Values were expressed as median (range) unless otherwise stated. Comparisons between two visits in the same group were performed by Wilcoxon paired rank test, while intergroup comparisons were performed by Mann-Whitney tests. The Fisher exact test was performed to determine the statistical relevance of the absence or presence of different gelatinolytic activities. The correlations between parameters were sought by calculating the Spearman correlation coefficient. p values of < 5% were considered to be statistically significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
FEV1 Variations After Allergen Challenge and Clinical Tolerance
In the asthmatic group, FEV1 was significantly reduced when compared to baseline at 5, 15, 30, 60, 300, and 360 min after the allergen inhalation (p < 0.05) [Fig 1 ]. Six asthmatic patients displayed a late phase, which was defined as a fall in FEV1 of > 15% 6 h after the allergen challenge. None of our patients experienced systemic symptoms such as fever or myalgia.



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  		Figure 1.. Mean FEV1, expressed as a baseline percentage, measured in allergic asthmatic patients after sham challenge ({circ}) and after allergen challenge (•). The error bar represents the SD. FEV1 expressed as baseline percentage was significantly reduced from baseline at 5, 15, 30, 60, 300, and 360 min after the inhalation of allergens.

 
Sputum Cell Counts and Albumin Levels
Each subject produced adequate sputum on both occasions. When compared to the sputum produced after a sham challenge, the cytology of the sputum produced 6 h after an allergen challenge was not modified in healthy control subjects, while the eosinophil counts increased significantly in allergic asthmatic patients (p < 0.01) [Table 2 ]. There were no significant differences regarding other cell counts between the sputum collected after sham challenge or allergen challenge in control subjects and asthmatic patients. Albumin levels were not significantly increased in the sputum of allergic asthmatic patients after allergen inhalation (Table 2) .


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  		Table 2.. Sputum Cytology and Biochemical Components*

 
Sputum MMP-9 and TIMP-1 Levels
Six hours after the allergen inhalation, MMP-9 levels, measured both by ELISA and zymography, significantly increased only in the group of asthmatic patients (p < 0.05) [Fig 2 ]. There were no significant differences in MMP-9 or TIMP-1 levels between the allergic asthmatic patients and control subjects in the sputum induction performed after sham challenge. Regarding TIMP-1, there was no significant increase after sham or allergen challenge, and no differences between the groups were detected. The molar ratio of MMP-9 to TIMP-1 increased after allergen challenge in the group of asthmatic patients, but this increase did not reach statistical significance (p = 0.08).



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  		Figure 2.. Top, A: MMP-9 measured by zymography 6 h after they underwent sham or allergen challenge. The results are expressed as arbitrary units. The horizontal bars represent the median values. Middle, B: MMP-9 measured by ELISA in the sputum of control subjects and allergic asthmatic patients 6 h after they underwent sham and allergen challenge. Bottom, C: TIMP-1 measured by ELISA in the sputum of control subjects and allergic asthmatic patients 6 h after they underwent sham or allergen challenge.

 
MMP Characterization in Zymography
All sputum from both asthmatic patients and control subjects showed bands at 92 kd, 72 kd, 130 kd, and 200 kd, respectively, corresponding to pro-MMP-9, pro-MMP-2, complexes between pro-MMP-9, and neutrophil-derived lipocalin and MMP-9 dimers. The bands related to MMP-9 comigrated with the bands of a neutrophil extract, which were used as a reference (data not shown). The activated form of MMP-9, which migrated at 85 kd, was detectable in three of five control subjects after sham challenge, in four of five control subjects after the allergen challenge, in four of eight asthmatic patients after sham challenge, and in six of eight asthmatic patients after allergen challenge (p > 0.05 for comparison of sham vs allergen challenge).

MMP-9 Levels Were Associated With FEV1 Variation
In allergic asthmatic patients, the maximal fall in FEV1 during the acute phase of the bronchospasm following allergen inhalation was significantly correlated with the MMP-9 levels measured in sputum by zymography (r = 0.51; p < 0.05) [Fig 3 ].



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  		Figure 3.. Top, A: correlation between sputum levels of MMP-9 and sputum neutrophil cell counts in allergic asthmatic patients 6 h after they underwent allergen challenge. Bottom, B: correlation between the sputum levels of MMP-9 and the maximal fall in FEV1 during the acute phase, expressed as the percentage decrease from baseline after allergen challenge.

 
Relationships Between MMP-9 Levels and Sputum Cytology
MMP-9 levels measured in sputum by ELISA were significantly correlated with the neutrophil percentages in asthmatic patients (r = 0.71; p < 0.01) [Fig 3 ].


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We found that after allergen inhalation, allergic asthmatic patients displayed a significant fall in FEV1, which was accompanied by an eosinophil influx in the airways. Concomitantly, the levels of MMP-9 were higher after allergen challenge than after sham challenge. By contrast, TIMP-1 levels were unaffected by the allergen challenge.

We chose to study patients with mild asthma who had a documented house dust mite allergy in order to investigate a homogeneous group of patients and to use the same relevant allergen. The allergen challenge that is performed by inhalation has the advantage of being closer to the physiologic mechanisms than the segmental allergen challenge and causes a measurable physiologic response (ie, the change in FEV1).

There are some concerns expressed in the literature about the fact that endotoxin may be a contaminant of the allergen preparation that is used for the challenge.17 In the present study, none of the patients experienced fever or general symptoms, and the levels of neutrophils did not rise significantly after the allergen challenge in control subjects or asthmatic patients. These findings, taken together with the fact that MMP-9 levels were not modified after allergen challenge in control subjects, indicate that a putative endotoxin contamination was not responsible for the observed biological effects.

In the present study, the basal secretion (after sham challenge) of MMP-9 and TIMP-1 was not increased in asthmatic patients when compared to control subjects. It has previously been reported4 6 that MMP-9 levels were increased in the basal state in the bronchial secretions of patients with asthma. In those studies, the conditions of the asthmatic patients were more severe, and they had impaired basal lung function. These differences in the patient characteristics may account for the absence of MMP-9 and TIMP-1 elevation in the bronchial secretions from asthmatic patients at baseline.

We found that the MMP-9 levels in the induced sputum after allergen inhalation were correlated with the percentages of neutrophils. This finding is consistent with the previous report of Becky Kelly et al,9 who demonstrated that such a relationship exists after segmental challenge and that the immunoreactivity to MMP-9 was mainly localized in neutrophils. The fact that the sputum samples displayed bands at 200 kd, 135 kd, and 85 kd, respectively corresponding to MMP-9 homodimers, MMP-9-neutrophil lipocalin complex, and activated MMP-9, is a strong indication that the MMP-9 detected after allergen challenge originates mainly from neutrophils. Indeed, these complexes are characteristics of neutrophil-derived MMP-9,18 19 and neutrophils have been identified as producing high amounts of MMP-9.18 Similar findings have been reported20 in the BAL fluid of patients with emphysema. Another argument supporting the fact that that MMP-9 originates from inflammatory cells rather than from plasma exudation is that the sputum levels of albumin are not significantly increased 6 h after allergen challenge in our study. There is striking evidence that MMP-9 is secreted during the neutrophil migration across the basement membrane,21 and we can speculate that the high levels of MMP-9 that are found in the sputum of asthmatic patients could derive partly from the process of activation of neutrophils. Interestingly, it has been demonstrated22 23 that the neutrophils express different types of IgE receptors and that their stimulation induces the activation of the cell and their degranulation. Moreover, the neutrophil influx in the airway lumen has been described as being increased as soon as 4 h after a segmental allergen challenge in asthma.24 Taken together, these data suggest an important role, perhaps triggered by IgE, for neutrophils in the acute reaction to inhaled allergens and suggest that these cells are likely to play a greater role in allergic inflammation than previously thought. Since we have demonstrated that MMP-9 is essential for the development of allergen-induced pulmonary inflammation and bronchial hyperresponsiveness in a mouse model of asthma,11 the present work confirms that MMP-9 probably plays an important role in the processes leading to inflammation following allergen exposure. However, in our mouse model of asthma, the short-term exposure did not induce significant remodeling of the airways, and studies over a longer period should be performed in order to determine whether MMP-9 is really implicated in the pathophysiology of bronchial remodeling. Other authors stressed the importance of epithelial cells in the response to inhaled allergens.25 In the present study, the number of epithelial cells was not significantly modified after allergen challenge, and there were no correlations between those cells and MMP-9 or TIMP-1 levels.

The sharp fall in FEV1 after allergen challenge is the consequence of short-term cell activation, leading to abundant mediator release. We found that MMP-9 levels were correlated with the variations in FEV1 that were measured during the allergen challenge. This correlation suggests that massive short-term cellular activation following allergen challenge may result in the secretion of large amounts of MMP-9 a few hours later.

Importantly, in the present study we did not find any increase of TIMP-1 after allergen challenge in asthmatic patients. This is not in accordance with the previous report of Becky Kelly et al,9 who described a significant elevation of TIMP-1 48 h after a segmental allergen challenge performed by bronchoscopy. In the processes leading to airway remodeling, consisting of extracellular matrix degradation and abnormal repair, we speculate that the inhaled allergens may lead to temporary increased proteolytic activity and that abnormal repair may occur after this initial degradation of some matrix components.

There are many differences between our study and the previous report of Becky Kelly et al9 that studied segmental challenges. First, we performed the sputum inductions 6 h after the allergen challenge in order to investigate the mediator release occurring during the late phase. Second, as discussed above, we chose to use inhaled allergens and induced sputum, the allergen inhalation being closer to the environmental exposure to the allergen than the segmental challenge performed during bronchoscopy. The compartments studied in the two studies are also different. In the present study, we sampled the major bronchi, and in the study by Becky Kelly et al9 the lower respiratory tract and the alveoli were sampled with BAL. The difference between the two studies regarding the elevation of TIMP-1 could be caused by methodological differences.

We conclude that the level of MMP-9, but not that of TIMP-1, is increased in the airways of asthmatic patients after they undergo an inhaled allergen challenge, leading to a relative imbalance between the protease and its inhibitor, which may initiate the processes that lead to airway remodeling in asthma patients.


   Acknowledgements
 
We thank Jocelyne Sele and Monique Henket for technical assistance.


   Footnotes
 
Abbreviations: ELISA = enzyme-linked immunosorbent assay; MMP = matrix metalloproteinases; PC20 = provocative concentration of a substance causing a 20% fall in FEV1; TIMP = tissue inhibitor of matrix metalloproteinase

{dagger} These authors should be considered equal contributors to the study. Back

This work was supported by Fonds National de la Recherche Scientifique (FNRS, Brussels, Belgium) grant FRSM 3.4603.98, the CGER-Assurance 1996/1999 grant, and the CHU, Liège, Belgium. Dr. Cataldo is a research fellow of the FNRS. Dr. Noël is a senior research associate of the FNRS.

Received for publication November 7, 2001. Accepted for publication May 28, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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