Relationship of airway wall thickening to an imbalance between matrix metalloproteinase-9 and its inhibitor in asthma

Abstract

Background:The balance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be critical in extracellular matrix remodelling, a characteristic of asthmatic airways. An excess of TIMP-1 over MMP-9 has been associated with chronic airflow obstruction but the mechanisms underlying this association remain unknown. Recent computed tomographic (CT) studies indicate that airway wall thickening is associated with chronic airflow obstruction. Methods: Sputum levels of MMP-9, TIMP-1, and their molar ratio were examined in 26 patients with stable asthma and their relationship with pulmonary function and airway wall thickness, assessed by a validated CT technique which measured wall area corrected by body surface area (WA/BSA), the ratio of WA to outer wall area (WA%), and the absolute wall thickness corrected by !BSA of a segmental bronchus (T/ !BSA), was examined. Results: Sputum MMP-9 levels were inversely correlated with WA% and TIMP-1 levels were positively correlated with WA/BSA and T/!BSA. The MMP-9/TIMP-1 molar ratio was inversely correlated with WA% and T/!BSA and positively correlated with post-bronchodilator values of mid-forced expiratory flow and maximum expiratory flow at the quartile of lung volume. Conclusion: Excess TIMP-1 may have a pathogenetic role in airway wall thickening in asthmatic patients which may result in chronic airflow obstruction.

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…In vitro and in vivo studies provide discordant findings: anyway, it appears clear that a too low MMP-9/TIMP-1 ratio results in airways wall thickness and impaired respiratory functions, whereas a too high in an excessive collagen III deposition in the sub-endothelial space and reduced elasticity (Matsumoto et al, 2005;Sands et al, 2009;Swartz et al, 2001;Todorova et al, 2010;Watson et al, 2010).…”

The contribution of transforming growth factor- and epidermal growth factor signalling to airway remodelling in chronic asthma

“…Additionally, CATALDO et al [70] reported that MMP-1 and TIMP-1 levels were increased at the mRNA level in induced sputum from asthmatic subjects compared with nonasthmatics. Recent studies using computed tomography have linked induced sputum MMP-9/TIMP-1 ratios to thickening of the airway wall in asthmatics [71,72].…”

The role of extracellular matrix metalloproteinases and their inhibitors in allergic diseases

“…Higher concentrations of MMP-9 in BALF correlate with the airway influx of neutrophils in patients subjected to antigen provocation and are, to a small degree, inhibited by oral glucocorticoids. Furthermore, a positive correlation was observed between MMP-9 and TIMP-1 concentrations and the number of neutrophils in the sputum of examined subjects [20,24].…”

“…The rate of collagen, proteoglycans, and elastin degradation was reduced due to the excess of TIMP-1 despite increased or normal activity of MMP-9 and was reflected by the bronchial wall accumulation of these compounds and resultant remodeling [23]. Matsumoto et al revealed a positive correlation between an increase in TIMP-1 concentration and the thickness of the bronchial wall in bronchial asthma patients, as well as the negative correlation between MMP-9/TIMP-1 ratio and the increase in airway wall thickness and irreversible obturation [24]. A proportional relationship was observed between MMP-9/TIMP-1 ratio in the induced sputum, or FEV1 of examined patients.…”