Effects of Inhaled Corticosteroids on Metalloproteinase-8 and Tissue Inhibitor of Metalloproteinase-1 in the Airways of Asthmatic Children

Abstract

Background: The effects of corticosteroids on the level and expression of matrix metalloproteinase-8 (MMP-8; collagenase-2) and tissue inhibitors of metalloproteinases (TIMPs) in airway tissue are poorly characterized in vivo. Methods: We compared MMP-8 and TIMP-1 levels in induced sputum and their expression in airway inflammatory cells of healthy children (n = 27) and of children with newly diagnosed asthma with mild (n = 20) or moderate symptoms (n = 19), before and after 6 months of treatment with inhaled budesonide. Results: At baseline, MMP-8 was higher in asthmatic children with moderate symptoms, TIMP-1 was lower and the MMP-8/TIMP-1 ratio was higher in both groups of asthmatic children compared with controls. Inhaled budesonide increased TIMP-1 levels in both groups of asthmatic children and normalized the MMP-8/TIMP-1 ratio, and this paralleled the improvement in forced expiratory volume in 1 s in children with mild symptoms. At baseline, asthmatic children had significantly more MMP-8-positive macrophages than control children, whereas the number of TIMP-1-positive macrophages was almost the same. Budesonide decreased the percentage of MMP-8-positive macrophages and increased that of TIMP-1-positive macrophages; these changes were significant in asthmatic children with mild symptoms. Conclusions: Inhaled budesonide normalized the MMP-8/TIMP-1 ratio in asthmatic children by upregulation of TIMP-1 production and downregulation of MMP-8 production by airway macrophages. This change may be a biochemical marker of an effect on airway inflammation and possibly of an ongoing remodeling process that should be further investigated using biopsy specimens.

Matrix Metalloproteinases Vary with Airway Microbiota Composition and Lung Function in Non–Cystic Fibrosis Bronchiectasis

“…This finding is consistent with research in other respiratory diseases, including CF, asthma, chronic obstructive pulmonary disease, and chronic bronchitis (19,(22)(23)(24)(25).…”

“…MMPs also have a diverse role in immunity that is not directly related to ECM modulation, including activation of cytokines, facilitation of cell migration, and activation of defensins (17). The ratios of individual MMPs to TIMPs have been reported to be informative in a number of other respiratory infections and diseases (18)(19)(20)(21)(22)(23)(24)(25); however, they have not been explored in bronchiectasis.…”

Evaluation of MMP-9 and TIMP-1 Levels of the Patients with Nasal Polyposis After Corticosteroid Therapies

“…In addition, Hoshino et al [22] reported that by reducing MMP-9 and increasing TIMP-1, corticosteroid treatment decreased the accumulation of subepithelial collagen in asthmatics. In another study [23] showed that inhaled budesonide normalized MMP-8/TIMP-1 ratio by reducing MMP-8 and increasing TIMP-1 in asthmatic children. In contrast to all above studies, all steroid treatment modalities had no effect on the levels of MMP-9 and TIMP-1 in our study.…”

Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal

“…Interestingly, MMP-13 levels were not detected in most of both healthy subjects and CAD patients [5, 29]. Corticosteroids were shown to repress the expression of MMP-8 [40]. Corticosteroids decreased MMP-8-positive eosinophils and macrophages and at the same time upregulated TIMP-1 from macrophages protecting the proteolytic effect of MMP-8 in the airways of asthmatic children [40].…”

“…Corticosteroids were shown to repress the expression of MMP-8 [40]. Corticosteroids decreased MMP-8-positive eosinophils and macrophages and at the same time upregulated TIMP-1 from macrophages protecting the proteolytic effect of MMP-8 in the airways of asthmatic children [40]. Glucocorticoid treatment downregulates the inflammatory genes through the activation of the glucocorticoid receptor, inhibits the cell expression of MMPs and activates the cellular expression of TIMPs.…”