Basic and Clinical Immunology
Subepithelial basement membrane immunoreactivity for matrix metalloproteinase 9: Association with asthma severity, neutrophilic inflammation, and wound repair

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Abstract

Background: Asthma likely involves an active injury and repair process, including components such as neutrophils and matrix metalloproteinase 9 (MMP-9). Although MMP-9 is increased in lavage fluid and sputum in patients with asthma, controversy exists as to the role of tissue MMP-9. Objective: The purpose of this study was to determine whether increases in submucosal cellular MMP-9, matrix MMP-9 (subepithelial basement membrane [SBM]), or both would be associated with severe asthma, neutrophilic inflammation, and wound repair. Methods: Immunohistochemical staining and analyses of MMP-9, inflammatory cells, transforming growth factor β, and collagen I were performed in endobronchial biopsy specimens, bronchoalveolar lavage fluid, or both from 38 patients with severe asthma and compared with results in 10 patients with mild asthma, 8 patients with moderate asthma, and 10 healthy control subjects. Results: A significantly greater proportion of patients with severe asthma demonstrated MMP-9 staining of the SBM than control subjects (P = .02). Bronchoalveolar lavage MMP-9 levels were also increased in patients with severe asthma (P = .0004). The numbers of submucosal neutrophils and macrophages, but not eosinophils, were significantly higher in asthmatic individuals with MMP-9 staining of the SBM (P = .004 and P = .01, respectively). However, the presence of SBM MMP-9 was associated with a high correlation between lavage and tissue eosinophils (r = 0.58, P = .009). Although the SBM thickness did not differ between groups, higher numbers of transforming growth factor β-positive cells were seen in subjects with SBM MMP-9 staining. Pulmonary function was significantly lower in those asthmatic subjects with SBM staining. Conclusions: These results suggest that localized tissue MMP-9 might play an important role in wound repair and cell trafficking. (J Allergy Clin Immunol 2003;111:1345-52.)

Section snippets

Subjects

Asthmatic subjects were divided into severity categories by using previously defined criteria.9 Briefly, patients with mild asthma all had a prebronchodilator FEV1 of greater than 80% of predicted value and were treated with as-needed β-agonists alone. Patients with moderate asthma had an FEV1 of less than 80% of predicted value, were taking low-to-moderate doses of inhaled corticosteroids plus as-needed β-agonists, and did not require oral steroids in the last year. Patients with severe asthma

Subjects

Thirty-eight patients with severe, 8 patients with moderate, and 10 patients with mild asthma and 10 healthy control subjects were evaluated with endobronchial biopsy and BAL. The baseline characteristics of these 66 subjects are given in Table I.

. Subject characteristics

Empty CellSubject characteristicsSteroid dose*
Sex (M/F)Age (y)*FEV1 (%)*Inhaled (μg)Oral (mg)
Normal5/537.3 ± 7102 ± 1100
Mild4/636.5 ± 9.289 ± 900
Moderate3/538.5 ± 13.165 ± 13660 ± 1100
Severe15/2334.9 ± 12.550 ± 181620 ± 22027 ± 7
*Mean ±

Discussion

This study suggests that both the location and the amount of MMP-9 immunoreactivity in the lung might be important in modifying wound-repair processes and associated clinical and physiologic outcomes in asthma. In patients with asthma, this MMP-9-mediated process appears to be associated with a specific type of tissue inflammation, with increased numbers of tissue neutrophils and macrophages, increased TGF-β+ cells, and worsened lung function. These associations were present when evaluating

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    Reprint requests: Sally E. Wenzel, MD, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206.

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