Am. J. Respir. Cell Mol. Biol., Volume 20, Number 5, May, 1999 903-913

Overexpression of Alveolar Macrophage Gelatinase B (MMP-9) in Patients with Idiopathic Pulmonary Fibrosis
Effects of Steroid and Immunosuppressive Treatment

Hassan Lemjabbar, Philippe Gosset, Emmanuelle Lechapt-Zalcman, Marie-Laure Franco-Montoya, Benoit Wallaert, Alain Harf, and Chantal Lafuma

INSERM U296 de Physiologie Respiratoire, Faculté de Médecine, Créteil; INSERM U416 de Pathologie Immuno-Allergologique Respiratoire, Institut Pasteur; and Service de Pneumologie et Immuno-Allergologie, Hôpital André, Calmette, Lille, France

Alveolar macrophages (AM) express gelatinase B, a member of the matrix metalloproteinase family involved in the degradation and remodeling of extracellular matrix components. We evaluated the expression of gelatinase B in the course of idiopathic pulmonary fibrosis (IPF) by studying alveolar macrophages in culture AM and bronchoalveolar lavage fluid from 12 untreated patients with IPF, 11 patients with IPF under treatment with steroid and immunosuppressive agents, and 10 control subjects. By using zymography and quantitative image analysis, latent gelatinase B, as well an 88-kD active form, were investigated in culture medium (24 h) of AMs and were found to be significantly increased (P < 0.01) in untreated patients exhibiting severe IPF when compared with control subjects (4.1 ± 1.7 versus 0.3 ± 0.2 10⁵ arbitrary units [AU]/10⁴ AM for the 92-kD form). Concomitant studies of gelatinase B levels associated with cultured AM extracts or freshly harvested AM showed similar results, both at the mRNA and protein levels, respectively. Immunocytochemical studies on freshly harvested AM demonstrated that the enzyme was located mainly at the cell, suggesting some involvement of gelatinase B in AM migration. In contrast, gelatinase B activity secreted by AM tended to be normal in patients with IPF under steroid and immunosuppressive treatment. Simultaneously, level of the gelatinase B activity in epithelial lining fluid was increased in untreated IPF patients, whereas it was normal in treated patients. These results suggest that AM of patients with IPF are primed for gelatinase B expression and that steroid and immunosuppressive treatment induces negative modulation of the gelatinase B overexpression. We conclude that gelatinase B may play a role in lung remodeling in IPF.

This article has been cited by other articles:

				J. W. Huh, D. S. Kim, Y.-M. Oh, T. S. Shim, C. M. Lim, S. D. Lee, Y. Koh, W. S. Kim, W. D. Kim, and K. R. Kim Is Metalloproteinase-7 Specific for Idiopathic Pulmonary Fibrosis? Chest, May 1, 2008; 133(5): 1101 - 1106. [Abstract] [Full Text] [PDF]

				M. Abel and H. Vliagoftis Mast Cell-Fibroblast Interactions Induce Matrix Metalloproteinase-9 Release from Fibroblasts: Role for IgE-Mediated Mast Cell Activation J. Immunol., March 1, 2008; 180(5): 3543 - 3550. [Abstract] [Full Text] [PDF]

				Y.-P. Han, C. Yan, L. Zhou, L. Qin, and H. Tsukamoto A Matrix Metalloproteinase-9 Activation Cascade by Hepatic Stellate Cells in Trans-differentiation in the Three-dimensional Extracellular Matrix J. Biol. Chem., April 27, 2007; 282(17): 12928 - 12939. [Abstract] [Full Text] [PDF]

				M. M. Kelly, R. Leigh, S. E. Gilpin, E. Cheng, G. E. M. Martin, K. Radford, G. Cox, and J. Gauldie Cell-specific Gene Expression in Patients with Usual Interstitial Pneumonia Am. J. Respir. Crit. Care Med., September 1, 2006; 174(5): 557 - 565. [Abstract] [Full Text] [PDF]

				A. Shukla, T. F. Barrett, K. I. Nakayama, K. Nakayama, B. T. Mossman, and K. M. Lounsbury Transcriptional up-regulation of MMP12 and MMP13 by asbestos occurs via a PKC{delta}-dependent pathway in murine lung FASEB J, May 1, 2006; 20(7): 997 - 999. [Abstract] [Full Text] [PDF]

				P T G Elkington and J S Friedland Matrix metalloproteinases in destructive pulmonary pathology Thorax, March 1, 2006; 61(3): 259 - 266. [Abstract] [Full Text] [PDF]

				M. Fujita, Q. Ye, H. Ouchi, E. Harada, I. Inoshima, K. Kuwano, and Y. Nakanishi Doxycycline Attenuated Pulmonary Fibrosis Induced by Bleomycin in Mice Antimicrob. Agents Chemother., February 1, 2006; 50(2): 739 - 743. [Abstract] [Full Text] [PDF]

				W. Matsuyama, M. Watanabe, Y. Shirahama, R. Hirano, H. Mitsuyama, I. Higashimoto, M. Osame, and K. Arimura Suppression of Discoidin Domain Receptor 1 by RNA Interference Attenuates Lung Inflammation J. Immunol., February 1, 2006; 176(3): 1928 - 1936. [Abstract] [Full Text] [PDF]

				A. Pardo and M. Selman Matrix metalloproteases in aberrant fibrotic tissue remodeling. Proceedings of the ATS, January 1, 2006; 3(4): 383 - 388. [Abstract] [Full Text] [PDF]

				W. Matsuyama, H. Mitsuyama, M. Watanabe, Y. Shirahama, I. Higashimoto, M. Osame, and K. Arimura Involvement of Discoidin Domain Receptor 1 in the Deterioration of Pulmonary Sarcoidosis Am. J. Respir. Cell Mol. Biol., December 1, 2005; 33(6): 565 - 573. [Abstract] [Full Text] [PDF]

				W. Matsuyama, M. Watanabe, Y. Shirahama, K.-i. Oonakahara, I. Higashimoto, T. Yoshimura, M. Osame, and K. Arimura Activation of Discoidin Domain Receptor 1 on CD14-Positive Bronchoalveolar Lavage Fluid Cells Induces Chemokine Production in Idiopathic Pulmonary Fibrosis J. Immunol., May 15, 2005; 174(10): 6490 - 6498. [Abstract] [Full Text] [PDF]

				A. E. Starr, T. Dan, K. Minhas, P. E. Shewen, and B. L. Coomber Potential Involvement of Gelatinases and Their Inhibitors in Mannheimia haemolytica Pneumonia in Cattle Infect. Immun., August 1, 2004; 72(8): 4393 - 4400. [Abstract] [Full Text] [PDF]

				I. I. Ekekezie, D. W. Thibeault, S. D. Simon, M. Norberg, J. D. Merrill, R. A. Ballard, P. L. Ballard, and W. E. Truog Low Levels of Tissue Inhibitors of Metalloproteinases With a High Matrix Metalloproteinase-9/Tissue Inhibitor of Metalloproteinase-1 Ratio Are Present in Tracheal Aspirate Fluids of Infants Who Develop Chronic Lung Disease Pediatrics, June 1, 2004; 113(6): 1709 - 1714. [Abstract] [Full Text] [PDF]

				L. G. Vazquez de Lara, T. M. Umstead, S. E. Davis, and D. S. Phelps Surfactant protein A increases matrix metalloproteinase-9 production by THP-1 cells Am J Physiol Lung Cell Mol Physiol, October 1, 2003; 285(4): L899 - L906. [Abstract] [Full Text] [PDF]

				T. Betsuyaku, K. Kadomatsu, G. L. Griffin, T. Muramatsu, and R. M. Senior Increased Basigin in Bleomycin-Induced Lung Injury Am. J. Respir. Cell Mol. Biol., May 1, 2003; 28(5): 600 - 606. [Abstract] [Full Text] [PDF]

				J. J. Atkinson and R. M. Senior Matrix Metalloproteinase-9 in Lung Remodeling Am. J. Respir. Cell Mol. Biol., January 1, 2003; 28(1): 12 - 24. [Abstract] [Full Text] [PDF]

				H.J. Bunn, G. Woltmann, and J. Grigg Applicability of laser scanning cytometry to study paediatric alveolar macrophages Eur. Respir. J., December 1, 2002; 20(6): 1437 - 1443. [Abstract] [Full Text] [PDF]

				M.T. Henry, K. McMahon, A.J. Mackarel, K. Prikk, T. Sorsa, P. Maisi, R. Sepper, M.X. FitzGerald, and C.M. O'Connor Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF Eur. Respir. J., November 1, 2002; 20(5): 1220 - 1227. [Abstract] [Full Text] [PDF]

				W. Eberhardt, E.-S. Akool, J. Rebhan, S. Frank, K.-F. Beck, R. Franzen, F. M. A. Hamada, and J. Pfeilschifter Inhibition of Cytokine-induced Matrix Metalloproteinase 9 Expression by Peroxisome Proliferator-activated Receptor alpha Agonists Is Indirect and Due to a NO-mediated Reduction of mRNA Stability J. Biol. Chem., August 30, 2002; 277(36): 33518 - 33528. [Abstract] [Full Text] [PDF]

				W. Eberhardt, M. Schulze, C. Engels, E. Klasmeier, and J. Pfeilschifter Glucocorticoid-Mediated Suppression of Cytokine-Induced Matrix Metalloproteinase-9 Expression in Rat Mesangial Cells: Involvement of Nuclear Factor-{kappa}B and Ets Transcription Factors Mol. Endocrinol., August 1, 2002; 16(8): 1752 - 1766. [Abstract] [Full Text] [PDF]

				R. G. Crystal, P. B. Bitterman, B. Mossman, M. I. Schwarz, D. Sheppard, L. Almasy, H. A. Chapman, S. L. Friedman, T. E. King Jr., L. A. Leinwand, et al. Future Research Directions in Idiopathic Pulmonary Fibrosis: Summary of a National Heart, Lung, and Blood Institute Working Group Am. J. Respir. Crit. Care Med., July 15, 2002; 166(2): 236 - 246. [Abstract] [Full Text] [PDF]

				L. Zheng, W.K. Lam, G.L. Tipoe, I.H. Shum, C. Yan, R. Leung, J. Sun, G.C. Ooi, and K.W. Tsang Overexpression of matrix metalloproteinase-8 and -9 in bronchiectatic airways in vivo Eur. Respir. J., July 1, 2002; 20(1): 170 - 176. [Abstract] [Full Text] [PDF]

				M. K. Winkler and J. L. Fowlkes Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis? Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L1 - L11. [Abstract] [Full Text] [PDF]

				K. H. Choi, H. B. Lee, M. Y. Jeong, Y. K. Rhee, M. J. Chung, Y. G. Kwak, and Y. C. Lee The Role of Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 in Cryptogenic Organizing Pneumonia* Chest, May 1, 2002; 121(5): 1478 - 1485. [Abstract] [Full Text] [PDF]

				F. Zuo, N. Kaminski, E. Eugui, J. Allard, Z. Yakhini, A. Ben-Dor, L. Lollini, D. Morris, Y. Kim, B. DeLustro, et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans PNAS, April 30, 2002; 99(9): 6292 - 6297. [Abstract] [Full Text] [PDF]

				K. Cederqvist, T. Sorsa, T. Tervahartiala, P. Maisi, K. Reunanen, P. Lassus, and S. Andersson Matrix Metalloproteinases-2, -8, and -9 and TIMP-2 in Tracheal Aspirates From Preterm Infants With Respiratory Distress Pediatrics, September 1, 2001; 108(3): 686 - 692. [Abstract] [Full Text] [PDF]

				C. Ramos, M. Montaño, J. García-Alvarez, V. Ruiz, B. D. Uhal, M. Selman, and A. Pardo Fibroblasts from Idiopathic Pulmonary Fibrosis and Normal Lungs Differ in Growth Rate, Apoptosis, and Tissue Inhibitor of Metalloproteinases Expression Am. J. Respir. Cell Mol. Biol., May 1, 2001; 24(5): 591 - 598. [Abstract] [Full Text]

				J. Araya, M. Maruyama, K. Sassa, T. Fujita, R. Hayashi, S. Matsui, T. Kashii, N. Yamashita, E. Sugiyama, and M. Kobayashi Ionizing radiation enhances matrix metalloproteinase-2 production in human lung epithelial cells Am J Physiol Lung Cell Mol Physiol, January 1, 2001; 280(1): L30 - L38. [Abstract] [Full Text] [PDF]

				T. Betsuyaku, Y. Fukuda, W. C. Parks, J. M. Shipley, and R. M. Senior Gelatinase B Is Required for Alveolar Bronchiolization after Intratracheal Bleomycin Am. J. Pathol., August 1, 2000; 157(2): 525 - 535. [Abstract] [Full Text] [PDF]

				W.-Y. Su, R. H. Jaskot, J. Richards, S. R. Abramson, J. F. Woessner Jr., W.-H. Yu, and K. L. Dreher Induction of pulmonary matrilysin expression by combustion and ambient air particles Am J Physiol Lung Cell Mol Physiol, July 1, 2000; 279(1): L152 - L160. [Abstract] [Full Text] [PDF]

				L. Segura-Valdez, A. Pardo, M. Gaxiola, B. D. Uhal, C. Becerril, and M. Selman Upregulation of Gelatinases A and B, Collagenases 1 and 2, and Increased Parenchymal Cell Death in COPD Chest, March 1, 2000; 117(3): 684 - 694. [Abstract] [Full Text] [PDF]