Occurrence of matrix metalloproteinases and tissue inhibitors of metalloproteinases in tuberculous pleuritis

doi:10.1054/tube.2000.0276

Tuberculosis

Volume 81, Issue 3, June 2001, Pages 203-209

https://doi.org/10.1054/tube.2000.0276 Get rights and content

Abstract

Objective: Matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) have been found in high concentrations in pleural effusions. Because MMP and TIMP may play a part in the causation of the fibrosis seen in tuberculous (TB) pleuritis their occurrence was examined.

Design: Pleural effusion fluid and plasma concentrations of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, TIMP-1 and TIMP-2 were determined by ELISA in 21 patients with TB pleuritis. To adjust for the total protein content, respective ratios were calculated. Activities of MMP-2 and MMP-9 were measured by gelatine zymography and the MMP-9/MMP-2 ratios calculated. Pleural effusions and plasma of 15 patients with congestive heat failure (CHF) and plasma of 15 healthy persons (CON) served as controls.

Results: Immunoreactive pleural fluid concentrations of MMP-1, MMP-2, MMP-8, and MMP-9 were higher in TB compared to CHF, but plasma concentrations were not different between the groups. TB pleural fluid concentrations of MMP-1, MMP-2, TIMP-1, and TIMP-2 were higher compared to TB plasma. MMP-3 was found in trace amounts only. The MMP-9/total protein ratios in pleural fluid were higher in TB compared to CHF (0.4492±0.1633 vs 0.0364±0.0145, P<0.005) but the TIMP-1 ratios were lower (139.0±28.7 vs 517.8±183.7, P<0.0005). In TB pleural fluid vs TB plasma, the respective MMP-1, MMP-2, TIMP-1, and TIMP-2 ratios were increased (0.46±0.10 vs 0.17±0.02; 25.2±2.8 vs 4.2±0.9; 139.0±28.7 vs 27.8±8.2; 0.67±0.13 vs 0.18±0.04, P<0.0005 each). Gelatine zymography demonstrated MMP-2 and MMP-9 bands of different brightness in TB effusions but in CHF effusions the MMP-9 band was barely visible. The MMP-9/MMP-2 effusion ratios were therefore higher in TB compared to CHF (0.46±0.15 vs 0.05±0.04,P <0.0005).

Conclusion: Compartmentalized MMP-1, MMP-2, TIMP-1, and TIMP-2 and, compared to CHF, a surplus of MMP-1, MMP-2, MMP-8, and MMP-9 in the pleural space obviously contribute to the fibrotic reactions in TB pleuritis.

References (35)

G Hoheisel et al.
Compartmentalization of proinflammatory cytokines in tuberculous pleurisy
Respir Medicine
(1998)
AN Hurewitz et al.
Human pleural effusions are rich in matrix metalloproteinases
Chest
(1992)
AN Hurewitz et al.
Tetracycline and doxycycline inhibit pleural fluid metalloproteinases
Chest
(1993)
SC Tyagi et al.
Direct extraction and estimation of collagenase(s) activity by zymography in microquantities of rat myocardium and uterus
Clin Biochem
(1993)
L Kjeldsen et al.
Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase
J Biol Chem
(1993)
M Lotz et al.
Interleukin-6 induces the synthesis of tissue inhibitor of metal-loproteinases-1/Erythroid potentiating activity (TIMP-1/EPA)
J Biol Chem
(1991)
M Lein et al.
Analytical aspects regarding the measurement of metalloproteinases and their inhibitors in blood
Clin Biochem
(1997)
JC Sibley
A study of 200 cases of tuberculous pleuritis with effusion
Am Rev Tuberc
(1950)
SA Sahn
The pleura
Am Rev Respir Dis
(1988)
RW Light
Tuberculous pleural effusions

J Ferrer

Pleural tuberculosis

Eur Respir J

(1997)

PF Barnes et al.

Compartmentalization of a CD4⁺T Lymphocyte subpopulation in tuberculous pleuritis

J Immunol

(1989)

VB Antony et al.

Recruitment of inflammatory cells to the pleural space

J Immunol

(1993)

PF Barnes et al.

Local production of tumor necrosis factor and IFN- γ in tuberculous pleuritis

J Immunol

(1990)

CHS Chan et al.

Clinical and pathological features of tuberculous pleural effusion and its long-term consequences

Respiration

(1991)

F Philip-Joët et al.

Fibrinolytic and inflammatory processes in pleural effusions

Eur Respir J

(1995)

G Hoheisel et al.

Procoagulant activity of PPD-stimulated pleural effusion mononuclear cells in tuberculous pleurisy

Respiration

(1997)

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^☆: This study was supported by: Grant 423/hk-rl, Deutscher Akademischer Auslandsdienst (DAAD)/Research Grants Council of Hong Kong (Hong Kong-German Joint Research Program); Förderverein Pneumologie, University of Leipzig; and Grant 01KS9504 A3, Interdisciplinary Centre for Clinical Research (IZKF), University of Leipzig.

^f1: Correspondence to: G. Hoheisel, Department of Internal Medicine, Pulmonary Unit, University of Leipzig, Johannisallee 32, D-04103 Leipzig, Germany. Tel.: +49 341 9712600; Fax: +49 341 9712609; E-mail: [email protected]

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Regular ArticleOccurrence of matrix metalloproteinases and tissue inhibitors of metalloproteinases in tuberculous pleuritis☆

Abstract

Respir Medicine

Chest

Chest

Clin Biochem

J Biol Chem

J Biol Chem

Clin Biochem

A study of 200 cases of tuberculous pleuritis with effusion

Am Rev Tuberc

The pleura

Am Rev Respir Dis

Tuberculous pleural effusions

Pleural tuberculosis

Eur Respir J

Compartmentalization of a CD4+T Lymphocyte subpopulation in tuberculous pleuritis

J Immunol

Recruitment of inflammatory cells to the pleural space

J Immunol

Local production of tumor necrosis factor and IFN- γ in tuberculous pleuritis

J Immunol

Clinical and pathological features of tuberculous pleural effusion and its long-term consequences

Respiration

Fibrinolytic and inflammatory processes in pleural effusions

Eur Respir J

Procoagulant activity of PPD-stimulated pleural effusion mononuclear cells in tuberculous pleurisy

Respiration

Regular Article
Occurrence of matrix metalloproteinases and tissue inhibitors of metalloproteinases in tuberculous pleuritis☆

Compartmentalization of a CD4⁺T Lymphocyte subpopulation in tuberculous pleuritis