The Role of Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 in Cryptogenic Organizing Pneumonia

Abstract

The processes observed in interstitial lung disease are associated with the production, deposition, and proteolysis of the extracellular matrix (ECM), which may lead to irreversible pulmonary structural remodeling or to appropriate repair without fibrosis. Matrix metalloproteinases (MMPs) and a tissue inhibitor of metalloproteinases (TIMPs) are known to regulate remodeling of the ECM and thus to be important in the process of lung fibrosis. Pulmonary structures are extensively remodeled in usual interstitial pneumonia (UIP), whereas severe architectural remodeling is minimally present in cryptogenic organizing pneumonia (COP). However, not much is known about the roles of MMP-9 and/or TIMP-1 in COP. Levels of MMP-9, TIMP-1 and the molar ratio of MMP-9/TIMP-1 in BAL fluids were investigated in 11 patients with UIP, in 8 patients with COP, and in 10 control subjects. We checked the levels of MMP-9 and TIMP-1 by means of enzyme immunoassay, and the hydrolytic activity of MMP-9 in BAL fluids was measured by gelatin zymography. Further, we evaluated the expression of MMP-9 and TIMP-1 in lung tissue by immunohistochemistry. The concentrations of MMP-9 and TIMP-1 were significantly increased in patients with UIP and were even higher in patients with COP compared with control subjects. The levels of MMP-9 and TIMP-1 were significantly higher in patients with COP than in patients with UIP. The molar ratio of MMP-9/TIMP-1 was significantly higher in patients with COP than in control subjects. In patients with COP, the concentration of MMP-9 significantly correlated with the number of neutrophils and lymphocytes. Zymographic analysis revealed that the activity of the 92-kd pro-MMP-9 was increased in patients with UIP and was even higher in patients with COP, compared with control subjects. These data suggest that overproduction of MMP-9 and TIMP-1, and an imbalance between MMP-9 and TIMP-1, may have a role as diagnostic references in COP.