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Chest

Volume 121, Issue 5, May 2002, Pages 1478-1485
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Clinical Investigations
Pneumonia
The Role of Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 in Cryptogenic Organizing Pneumonia

https://doi.org/10.1378/chest.121.5.1478Get rights and content

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Section snippets

Subjects

Study subjects included 11 patients with UIP, 8 patients with COP, and 10 normal control subjects (Table 1). The diagnosis of interstitial lung disease was based on the presence of progressive breathlessness, bilateral dry crackles, widespread bilateral infiltrates in chest radiographs, and pulmonary function test results showing a reduced total lung capacity (TLC), reduced FVC, decreased single-breath diffusion capacity of the lung for carbon monoxide (Dlco), and resting hypoxemia. Histologic

Results

The mean age and sex of patients with UIP and COP and of control subjects in this study were similar (Table 1). Values for FVC, FEV1/FVC, TLC, and Dlco were significantly lower in patients with COP and in patients with UIP than in control subjects (all p < 0.01). The values for FEV1/FVC, Dlco, and TLC were also significantly different between patients with COP and patients with UIP (all p < 0.01). The recovery rates of BAL fluids in patients with COP, in patients with UIP, and in control

Discussion

In this study, we have demonstrated that levels 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.

MMPs are capable of degrading various components of the connective tissue matrix, and TIMPs are

References (33)

  • B Ricou et al.

    Matrix metalloproteinase and TIMP in acute respiratory distress syndrome

    Am J Respir Crit Care Med

    (1996)
  • K Torii et al.

    Higher concentrations of matrix metalloproteinases in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome

    Am J Respir Crit Care Med

    (1997)
  • GA Finlay et al.

    Matrix metalloproteinase expression and production by alveolar macrophages in emphysema

    Am J Respir Crit Care Med

    (1997)
  • RL Warner et al.

    Role of stromelysin 1 and gelatinase B in experimental acute lung injury

    Am J Respir Cell Mol Biol

    (2001)
  • S Okada et al.

    Migration of eosinophils through basement membrane components in vitro: role of matrix metalloproteinase-9

    Am J Respir Cell Mol Biol

    (1997)
  • C Delclaux et al.

    Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across the basement membrane

    Am J Respir Cell Mol Biol

    (1996)

    • Cited by (0)

    Supported by grant No. 2000–1-21200–001-3 from the Basic Research Program of the Korea Science and Engineering Foundation, and by the Brain Korea 21 Project in 2001.

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    Copyright © 2002 The American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.