Bronchoalveolar Lavage MMP-9 and TIMP-1 in Preschool Wheezers and Their Relationship to Persistent Wheeze

Abstract

Atopic preschool children are more likely to develop persistent wheezing, which could be a consequence of early airway remodeling. Protease-antiprotease balance between MMP-9 and its cognate inhibitor TIMP-1 may be involved in this process. Our hypothesis was that atopic wheezing preschool children would have an imbalance of MMP-9 to TIMP-1 in bronchoalveolar lavage (BAL). BAL from 52 preschool wheezers was compared with 14 controls without wheeze. A subgroup completed an International Study of Asthma and Allergy in Childhood symptom questionnaire 2 y later. Molar ratios of MMP-9/TIMP-1 were higher in wheezy children (p Ͻ 0.001; median 4.0%, range 0 -8.7) than controls (0.6%, 0 -1.8), and showed an excess of TIMP-1 in the airway. BAL TIMP-1 was raised in children with persistent wheezing (p ϭ 0.028; 34.4 ng/mL, 9.1-93.1 compared with 10.6 ng/mL 6.1-18.6), as was serum levels of intercellular adhesion molecule-1 (p ϭ 0.027). The absolute concentration of TIMP-1 in the airway, rather than its molar ratio with MMP-9, was associated with persistent wheezing. The processes involved with airway remodeling are complex but excess TIMP-1 may impede matrix protein turnover and thereby contribute to persistent changes in airway structure and wheezing. W heezing is a common respiratory symptom among preschool children and while most outgrow their disease by mid childhood, some continue to wheeze and develop asthma. Atopic preschool children are more likely to have persistent wheezing associated with progressively reducing pulmonary function (1). The cause of this deteriorating pulmonary function is not known, but airway remodeling is implicated in the disease process, and has been found in school-aged children with asthma (2-6). Thickening of the epithelial basement membrane (EBM) is an age related event detectable by 3 y of age in severe recurrent wheezers (7,8).Although the inflammatory mechanisms underlying the remodeling process are not known, protease anti-protease balance is one factor that could lead to a disorder of matrix turnover (9). The matrixins are a family of proteases able to digest components of the extracellular matrix (ECM). Matrix metalloproteinase 9 (MMP-9) is the predominant matrixin in pulmonary tissue and is specifically inhibited by tissue inhibitor of metalloproteinase-1 (TIMP-1) in a 1:1 ratio (10). There are two opposing mechanisms by which MMP-9 and TIMP-1 could affect a remodeling process: First, an excess of active MMP-9 over TIMP-1 would allow unregulated destruction of the ECM leading to inflammation and wound repair (11). Second, an excess of TIMP-1 over MMP-9 would slow the turnover of the ECM, which may include thickening of the EBM.Although, there is accumulating evidence of a role for MMP-9 and TIMP-1 in adult asthma (11-16), there are conflicting results in children, in an age group where structural remodeling may actually be occurring (17,18). The aim of this study was to investigate MMP-9 and TIMP-1 in bronchoalveolar lavage (BAL) from preschool wheezers. Our hypotheses wer...

Severe Persistent Allergic Rhinitis. Inflammation but No Histologic Features of Structural Upper Airway Remodeling

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IL-5, IL-8 and MMP -9 levels in exhaled breath condensate of atopic and nonatopic asthmatic children

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Shifting of Immune Responsiveness to House Dust Mite by Influenza A Infection: Genomic Insights

“…In addition to the increased expression of several members of the chemokine and cytokine family and genes encoding additional complement components, we particularly observed increased expression of genes encoding proteins, such as Saa3, Timp1, and serine peptidase inhibitor, clade A, member 3N (Serpina3n). Although Timp1 was reported to play a role in extracellular matrix remodeling, and its role in the development of allergic asthma is well described (30,31), the functional role of Serpina3n has not been established. In humans, SERPIN3A, commonly known as antichymotrypsin, is produced by a variety of cell types, including hepatocytes and bronchial epithelial cells during acute inflammatory responses, and studies showed that serum levels of two other serpin family members, SERPINB3 and SERPINB4, are elevated in patients with asthma (32,33).…”