Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases mRNA transcripts in the bronchial secretions of asthmatics

Abstract

Asthma is a chronic inflammatory disease characterized by profound extracellular matrix changes referred to as bronchial remodelling. In this study, we evaluated matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) mRNA expression in bronchial secretions of asthmatics and correlated MMPs modulations with the lung function as a reflection of the bronchial extracellular matrix remodelling. Quantitative RT-PCR was performed on cell pellets obtained from induced sputum in order to detect the mRNAs for MMP-1, -2, -3, -8, -9, -12, -13 TIMP-1, -2, while semiquantitative RT-PCR was performed to assess the expression of MMP-7, monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-b 1 (TGF-b 1 ). The mRNA transcripts for MMP-1, TIMP-1 and monocyte chemoattractant protein-1 (MCP-1) were increased in cell pellets of induced sputum from asthmatics when compared to controls (Po0.05), and the intensity of MMP-1 mRNA expression inversely correlated with the FEV 1 in asthmatics (r ¼ À0.49, Po0.05). The MMP-1 mRNA/TIMP-1 mRNA ratio correlated with the levels of MCP-1 mRNA in asthmatics (r ¼ 0.47, Po0.05). There were no differences between the groups with respect to mRNA coding for MMP-2, -3, -7, -8, -9, -12, -13, -14, TIMP-2 and TGF-b 1 . We conclude that cells contained in the bronchial secretions from asthmatics express higher amounts of mRNA for MMP-1 and TIMP-1, perhaps related to an increased expression of MCP-1, which might contribute to the extracellular matrix changes observed during airway remodelling.

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: Potential implications in asthma and other lung diseases

“…However, other authors studying such fluids (bronchoalveolar lavage or induced sputum) or bronchial wall did not report such an imbalance suggesting that bronchial inflammation would lead to a proteolytic burden followed by scar formation resulting in a disorganised extracellular matrix (Cataldo et al, 2002a;Hoshino et al, 1999;Kelly et al, 2000). Moreover, in asthmatics, TIMP-1 was reported to be secreted in a lesser extent by granulocytes suggesting that it could exist an imbalance between proteolytic and anti-proteolytic activities at the pericellular level in the airway wall (Cataldo et al, 2002a;Hoshino et al, 1999;Kelly et al, 2000).…”

“…MMP-9 levels were increased after allergen challenge in the sputum from allergic asthmatics as compared to control subjects and correlated to the percentage of eosinophils while TIMP-1 levels did not vary significantly (Cataldo et al, 2002a;Kelly et al, 2000). This observation suggests that extracellular matrix can be aggressed after allergen contact and are linked to allergen-induced acute bronchial inflammation.…”

“…Monocyte chemoat-tractant protein-1 (MCP-1) contributes undoubtfully to extracellular matrix changes observed during airway remodeling by increasing the mRNA for MMP-1 and TIMP-1 expression in cells from the bronchial secretions in asthmatics (Cataldo et al, 2002a). IL-1β, a pro-inflammatory cytokine, is increased in lungs of patients with asthma and is converted from its latent form by different proteases including MMP-9 (Schonbeck et al, 1998).…”

“…Although the interest of investigating a balance between MMP-9 and TIMP-1 would probably be restricted to the pericellular area, some authors have reported an imbalance observed between MMP-9 and TIMP-1 measured in bronchial secretions or bronchoalveolar lavage, with a significant increase of TIMP-1 production when compared to that of MMP-9, thought to favouring extracellular matrix deposition (Mautino et al, 1999;Vignola et al, 1998b). However, other authors studying such fluids (bronchoalveolar lavage or induced sputum) or bronchial wall did not report such an imbalance suggesting that bronchial inflammation would lead to a proteolytic burden followed by scar formation resulting in a disorganised extracellular matrix (Cataldo et al, 2002a;Hoshino et al, 1999;Kelly et al, 2000). Moreover, in asthmatics, TIMP-1 was reported to be secreted in a lesser extent by granulocytes suggesting that it could exist an imbalance between proteolytic and anti-proteolytic activities at the pericellular level in the airway wall (Cataldo et al, 2002a;Hoshino et al, 1999;Kelly et al, 2000).…”

“…However, other authors studying such fluids (bronchoalveolar lavage or induced sputum) or bronchial wall did not report such an imbalance suggesting that bronchial inflammation would lead to a proteolytic burden followed by scar formation resulting in a disorganised extracellular matrix (Cataldo et al, 2002a;Hoshino et al, 1999;Kelly et al, 2000). Moreover, in asthmatics, TIMP-1 was reported to be secreted in a lesser extent by granulocytes suggesting that it could exist an imbalance between proteolytic and anti-proteolytic activities at the pericellular level in the airway wall (Cataldo et al, 2002a;Hoshino et al, 1999;Kelly et al, 2000).MMP-9 levels were increased after allergen challenge in the sputum from allergic asthmatics as compared to control subjects and correlated to the percentage of eosinophils while TIMP-1 levels did not vary significantly (Cataldo et al, 2002a;Kelly et al, 2000). This observation suggests that extracellular matrix can be aggressed after allergen contact and are linked to allergen-induced acute bronchial inflammation.…”