Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF

Abstract

The purpose of this study was to examine the role of interstitial collagenases, members of the family of matrix metalloproteinases, in the development of pulmonary fibrosis.The activity, levels and molecular forms of collagenases (matrix metalloproteinases (MMP)-1, -8 and -13), gelatinase B (MMP-9) and its main endogenous inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) and sarcoidosis patients with varying degrees of pulmonary parenchymal involvement.Collagenase activity was elevated in IPF and group 3 sarcoidosis patients. A positive correlation between BALF collagenase activity and MMP-8 levels was also observed. Western immunoblotting revealed the presence of two isoforms of MMP-8 in patient samples; an 80 kD form representing latent enzyme from polymorphonuclear neutrophils and a 55 kD form representing the fibroblast-type proform. MMP-9 levels were also elevated in both IPF and group 3 sarcoidosis patients, while TIMP-1 levels remained normal, indicating a shift in the balance between the enzyme and inhibitor, favouring MMP-9.Matrix metalloproteinase-8 is the major contributor to the bronchoalveolar lavage fluid collagenase activity in the airways of patients with idiopathic pulmonary fibrosis and sarcoidosis and may initiate collagen destruction and remodelling leading to the development of pulmonary fibrosis.

Lung dysfunction causes systemic hypoxia in estrogen receptor β knockout (ERβ −/− ) mice

“…Dysregulation of caveolin-1 expression can lead to dispersion of MT1-MMP from the lipid rafts of the plasma membrane, and this can interfere with several of the enzymatic activities of MT1-MMP (21). We speculate that ER␤ regulates both the expression of MT1-MMP and its localization on the lipid rafts of the plasma membrane.…”

“…Recent data have revealed a major role for MMPs in normal lung development and maintenance of lung architecture (13)(14)(15)(16)(17). Despite their key role in repair of the lung, MMPs can lead to destruction of alveolar epithelium, and overactivity of MMPs in the lung is thought to contribute to pulmonary diseases such as emphysema, idiopathic interstitial pneumonias, chronic obstructive pulmonary disease, and chronic reactive airway disease (18)(19)(20)(21). MMPs are also involved in the invasion process of several metastatic cancer cells.…”

Interfering with extracellular matrix degradation to blunt inflammation

“…MMP's -1, 2, 8 and 9 have also been demonstrated to be elevated in asthmatic airways albeit to a lesser extent than in COPD [20]. Increased expression of MMPs-8, 9 and 7 has been demonstrated in the fibrosing diseases, IPF and pulmonary sarcoidosis [21][22][23][24].…”

Serum biomarkers in idiopathic pulmonary fibrosis

“…Matrix degrading enzymes of the MMP family are thought to be critically involved in the deposition and remodeling of the extracellular matrix, as observed in pulmonary fibrosis [59][60][61]. A genetic polymorphism in the MMP1 promotor was linked to IPF in smoking individuals [62].…”