This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Atkinson, J. J. Articles by Senior, R. M. Search for Related Content PubMed PubMed Citation Articles by Atkinson, J. J. Articles by Senior, R. M.

Matrix Metalloproteinase-9 in Lung Remodeling

Pulmonary and Critical Care Medicine, Department of Medicine, and the Department of Cell Biology and Physiology, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri

Address correspondence to: Robert M. Senior, M.D., Barnes-Jewish Hospital (North), 216 South Kingshighway, St. Louis, MO, 63110. E-mail: seniorr{at}msnotes.wustl.edu

Matrix metalloproteinase (MMP)-9 (Gelatinase B, 92-kD type IV collagenase, EC 3.4.24.35) is an MMP that is present in low quantities in the healthy adult lung, but much more abundant in several lung diseases, including asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD). Despite numerous reports of MMP-9 in these and other lung diseases, whether MMP-9 is causal in lung remodeling or part of the inflammatory and reparative response remains to be determined. Many intrinsic lung cells can be stimulated to produce MMP-9, but much of the information regarding MMP-9 in the lung deals with MMP-9 from inflammatory cells. The multiple locations and cell types producing MMP-9 are consistent with multiple functions in different microenvironments. In addition to digestion of structural proteins and antiproteases, MMP-9 can modify cellular function by regulation of cytokines and matrix-bound growth factors. Determining the role of MMP-9 in health and disease will be important, because broad spectrum and specific inhibitors will soon be available to enable conversion of the bench knowledge to bedside practice. This review addresses the current understanding of MMP-9 in human asthma, IPF, and COPD, and in animal models of these conditions.

Abbreviations: bronchoalveolar lavage fluid, BALF • bronchiolitis obliterans organizing pneumonia, BOOP • chronic obstructive pulmonary disease, COPD • extracellular matrix, ECM • enzyme linked immunoabsorbant assay, ELISA • forced expiratory volume at one second, FEV₁ • interleukin, IL • interstitial pulmonary fibrosis, IPF • matrix metalloproteinase, MMP • reverse transcriptase–polymerase chain reaction, RT-PCR • tissue inhibitor of matrix metalloproteinase, TIMP • transforming growth factor, TGF • tumor necrosis factor, TNF

This article has been cited by other articles:

				R. Foronjy, T. Nkyimbeng, A. Wallace, J. Thankachen, Y. Okada, V. Lemaitre, and J. D'Armiento Transgenic expression of matrix metalloproteinase-9 causes adult-onset emphysema in mice associated with the loss of alveolar elastin Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1149 - L1157. [Abstract] [Full Text] [PDF]

				S. Tsujimura, K. Saito, S. Nakayamada, and Y. Tanaka Bolus infusion of human urinary trypsin inhibitor improves intractable interstitial pneumonia in patients with connective tissue diseases Rheumatology, June 1, 2008; 47(6): 907 - 913. [Abstract] [Full Text] [PDF]

				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]

				H. S. Deshmukh, C. Shaver, L. M. Case, M. Dietsch, S. C. Wesselkamper, W. D. Hardie, T. R. Korfhagen, M. Corradi, J. A. Nadel, M. T. Borchers, et al. Acrolein-Activated Matrix Metalloproteinase 9 Contributes to Persistent Mucin Production Am. J. Respir. Cell Mol. Biol., April 1, 2008; 38(4): 446 - 454. [Abstract] [Full Text] [PDF]

				H. R. Collard, B. B. Moore, K. R. Flaherty, K. K. Brown, R. J. Kaner, T. E. King Jr., J. A. Lasky, J. E. Loyd, I. Noth, M. A. Olman, et al. Acute Exacerbations of Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., October 1, 2007; 176(7): 636 - 643. [Abstract] [Full Text] [PDF]

				C. M. Swaisgood, M. A. Aronica, S. Swaidani, and E. F. Plow Plasminogen Is an Important Regulator in the Pathogenesis of a Murine Model of Asthma Am. J. Respir. Crit. Care Med., August 15, 2007; 176(4): 333 - 342. [Abstract] [Full Text] [PDF]

				A. Churg, R. Wang, X. Wang, P.-O. Onnervik, K. Thim, and J. L Wright Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs Thorax, August 1, 2007; 62(8): 706 - 713. [Abstract] [Full Text] [PDF]

				K. Pochetuhen, I. G. Luzina, V. Lockatell, J. Choi, N. W. Todd, and S. P. Atamas Complex Regulation of Pulmonary Inflammation and Fibrosis by CCL18 Am. J. Pathol., August 1, 2007; 171(2): 428 - 437. [Abstract] [Full Text] [PDF]

				T. Yoshida and R. M. Tuder Pathobiology of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease Physiol Rev, July 1, 2007; 87(3): 1047 - 1082. [Abstract] [Full Text] [PDF]

				M. Marcet-Palacios, M. Ulanova, F. Duta, L. Puttagunta, S. Munoz, D. Gibbings, M. Radomski, L. Cameron, I. Mayers, and A. D. Befus The Transcription Factor Wilms Tumor 1 Regulates Matrix Metalloproteinase-9 through a Nitric Oxide-Mediated Pathway J. Immunol., July 1, 2007; 179(1): 256 - 265. [Abstract] [Full Text] [PDF]

				S. Ivanov, S. Bozinovski, A. Bossios, H. Valadi, R. Vlahos, C. Malmhall, M. Sjostrand, J. K. Kolls, G. P. Anderson, and A. Linden Functional Relevance of the IL-23-IL-17 Axis in Lungs In Vivo Am. J. Respir. Cell Mol. Biol., April 1, 2007; 36(4): 442 - 451. [Abstract] [Full Text] [PDF]

				C.-W. Lee, C.-C. Lin, W.-N. Lin, K.-C. Liang, S.-F. Luo, C.-B. Wu, S.-W. Wang, and C.-M. Yang TNF-{alpha} induces MMP-9 expression via activation of Src/EGFR, PDGFR/PI3K/Akt cascade and promotion of NF-{kappa}B/p300 binding in human tracheal smooth muscle cells Am J Physiol Lung Cell Mol Physiol, March 1, 2007; 292(3): L799 - L812. [Abstract] [Full Text] [PDF]

				P. F. Bove, U. V. Wesley, A.-K. Greul, M. Hristova, W. R. Dostmann, and A. van der Vliet Nitric Oxide Promotes Airway Epithelial Wound Repair through Enhanced Activation of MMP-9 Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 138 - 146. [Abstract] [Full Text] [PDF]

				K. J. Greenlee, Z. Werb, and F. Kheradmand Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted Physiol Rev, January 1, 2007; 87(1): 69 - 98. [Abstract] [Full Text] [PDF]

				Y. Ozawa, H. Kobori, Y. Suzaki, and L. G. Navar Sustained renal interstitial macrophage infiltration following chronic angiotensin II infusions Am J Physiol Renal Physiol, January 1, 2007; 292(1): F330 - F339. [Abstract] [Full Text] [PDF]

				E. K. Chu, J. Cheng, J. S. Foley, B. H. Mecham, C. A. Owen, K. J. Haley, T. J. Mariani, I. S. Kohane, D. J. Tschumperlin, and J. M. Drazen Induction of the Plasminogen Activator System by Mechanical Stimulation of Human Bronchial Epithelial Cells Am. J. Respir. Cell Mol. Biol., December 1, 2006; 35(6): 628 - 638. [Abstract] [Full Text] [PDF]

				Q. Fang, X. Liu, M. Al-Mugotir, T. Kobayashi, S. Abe, T. Kohyama, and S. I. Rennard Thrombin and TNF-{alpha}/IL-1beta Synergistically Induce Fibroblast-Mediated Collagen Gel Degradation Am. J. Respir. Cell Mol. Biol., December 1, 2006; 35(6): 714 - 721. [Abstract] [Full Text] [PDF]

				K. J. Greenlee, D. B. Corry, D. A. Engler, R. K. Matsunami, P. Tessier, R. G. Cook, Z. Werb, and F. Kheradmand Proteomic Identification of In Vivo Substrates for Matrix Metalloproteinases 2 and 9 Reveals a Mechanism for Resolution of Inflammation J. Immunol., November 15, 2006; 177(10): 7312 - 7321. [Abstract] [Full Text] [PDF]

				M. Suzukawa, A. Komiya, M. Iikura, H. Nagase, C. Yoshimura-Uchiyama, H. Yamada, H. Kawasaki, K. Ohta, K. Matsushima, K. Hirai, et al. Trans-basement membrane migration of human basophils: role of matrix metalloproteinase-9 Int. Immunol., November 1, 2006; 18(11): 1575 - 1583. [Abstract] [Full Text] [PDF]

				M. M. Choe, P. H. S. Sporn, and M. A. Swartz Extracellular Matrix Remodeling by Dynamic Strain in a Three-Dimensional Tissue-Engineered Human Airway Wall Model Am. J. Respir. Cell Mol. Biol., September 1, 2006; 35(3): 306 - 313. [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]

				L. de Franceschi, G. Malpeli, A. Scarpa, A. Janin, E. M. Muchitsch, P. Roncada, C. Leboeuf, R. Corrocher, Y. Beuzard, and C. Brugnara Protective effects of S-nitrosoalbumin on lung injury induced by hypoxia-reoxygenation in mouse model of sickle cell disease Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L457 - L465. [Abstract] [Full Text] [PDF]

				D. H. Lim, J. Y. Cho, M. Miller, K. McElwain, S. McElwain, and D. H. Broide Reduced peribronchial fibrosis in allergen-challenged MMP-9-deficient mice. Am J Physiol Lung Cell Mol Physiol, August 1, 2006; 291(2): L265 - L271. [Abstract] [Full Text] [PDF]

				L. Zhang, M. Ikegami, T. R. Korfhagen, F. X. McCormack, M. Yoshida, R. M. Senior, J. M. Shipley, S. D. Shapiro, and J. A. Whitsett Neither SP-A nor NH2-terminal domains of SP-A can substitute for SP-D in regulation of alveolar homeostasis Am J Physiol Lung Cell Mol Physiol, August 1, 2006; 291(2): L181 - L190. [Abstract] [Full Text] [PDF]

				D. S. Postma and W. Timens Remodeling in asthma and chronic obstructive pulmonary disease. Proceedings of the ATS, July 1, 2006; 3(5): 434 - 439. [Abstract] [Full Text] [PDF]

				L. P. Nicod Mechanisms of airway obliteration after lung transplantation. Proceedings of the ATS, July 1, 2006; 3(5): 444 - 449. [Abstract] [Full Text] [PDF]

				K. Koli, M. Myllarniemi, K. Vuorinen, K. Salmenkivi, M. J. Ryynanen, V. L. Kinnula, and J. Keski-Oja Bone Morphogenetic Protein-4 Inhibitor Gremlin Is Overexpressed in Idiopathic Pulmonary Fibrosis Am. J. Pathol., July 1, 2006; 169(1): 61 - 71. [Abstract] [Full Text] [PDF]

				J.-H. Kim, J.-H. Jeong, S.-T. Jeon, H. Kim, J. Ock, K. Suk, S.-I. Kim, K.-S. Song, and W.-h. Lee Decursin Inhibits Induction of Inflammatory Mediators by Blocking Nuclear Factor-{kappa}B Activation in Macrophages Mol. Pharmacol., June 1, 2006; 69(6): 1783 - 1790. [Abstract] [Full Text] [PDF]

				E. Lechapt-Zalcman, V. Pruliere-Escabasse, D. Advenier, S. Galiacy, C. Charriere-Bertrand, A. Coste, A. Harf, M.-P. d'Ortho, and E. Escudier Transforming growth factor-beta1 increases airway wound repair via MMP-2 upregulation: a new pathway for epithelial wound repair? Am J Physiol Lung Cell Mol Physiol, June 1, 2006; 290(6): L1277 - L1282. [Abstract] [Full Text] [PDF]

				E. Adelroth, U. Hedlund, A. Blomberg, R. Helleday, M-C. Ledin, J. O. Levin, J. Pourazar, T. Sandstrom, and B. Jarvholm Airway inflammation in iron ore miners exposed to dust and diesel exhaust Eur. Respir. J., April 1, 2006; 27(4): 714 - 719. [Abstract] [Full Text] [PDF]

				P. C. Frake, H. E. Smith, L.-F. Chen, and W. L. Biffl Prestorage Leukoreduction Prevents Accumulation of Matrix Metalloproteinase 9 in Stored Blood Arch Surg, April 1, 2006; 141(4): 396 - 400. [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]

				S. J. Park, M. T. Wiekowski, S. A. Lira, and B. Mehrad Neutrophils Regulate Airway Responses in a Model of Fungal Allergic Airways Disease J. Immunol., February 15, 2006; 176(4): 2538 - 2545. [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]

				I. Mookerjee, N. R. Solly, S. G. Royce, G. W. Tregear, C. S. Samuel, and M. L. K. Tang Endogenous Relaxin Regulates Collagen Deposition in an Animal Model of Allergic Airway Disease Endocrinology, February 1, 2006; 147(2): 754 - 761. [Abstract] [Full Text] [PDF]

				H. B. Acuff, K. J. Carter, B. Fingleton, D. L. Gorden, and L. M. Matrisian Matrix Metalloproteinase-9 from Bone Marrow-Derived Cells Contributes to Survival but not Growth of Tumor Cells in the Lung Microenvironment Cancer Res., January 1, 2006; 66(1): 259 - 266. [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]

				F. B. Santos, L. K. S. Nagato, N. M. Boechem, E. M. Negri, A. Guimaraes, V. L. Capelozzi, D. S. Faffe, W. A. Zin, and P. R. M. Rocco Time course of lung parenchyma remodeling in pulmonary and extrapulmonary acute lung injury J Appl Physiol, January 1, 2006; 100(1): 98 - 106. [Abstract] [Full Text] [PDF]

				S. Chakrabarti, J. M. Zee, and K. D. Patel Regulation of matrix metalloproteinase-9 (MMP-9) in TNF-stimulated neutrophils: novel pathways for tertiary granule release J. Leukoc. Biol., January 1, 2006; 79(1): 214 - 222. [Abstract] [Full Text] [PDF]

				I. Ito, S. Nagai, T. Handa, S. Muro, T. Hirai, M. Tsukino, and M. Mishima Matrix Metalloproteinase-9 Promoter Polymorphism Associated with Upper Lung Dominant Emphysema Am. J. Respir. Crit. Care Med., December 1, 2005; 172(11): 1378 - 1382. [Abstract] [Full Text] [PDF]

				W. MacNee Pathogenesis of Chronic Obstructive Pulmonary Disease Proceedings of the ATS, November 1, 2005; 2(4): 258 - 266. [Abstract] [Full Text] [PDF]

				X. Lian, C. Yan, Y. Qin, L. Knox, T. Li, and H. Du Neutral Lipids and Peroxisome Proliferator-Activated Receptor-{gamma} Control Pulmonary Gene Expression and Inflammation-Triggered Pathogenesis in Lysosomal Acid Lipase Knockout Mice Am. J. Pathol., September 1, 2005; 167(3): 813 - 821. [Abstract] [Full Text] [PDF]

				X. Lian, Y. Qin, S. A. Hossain, L. Yang, A. White, H. Xu, J. M. Shipley, T. Li, R. M. Senior, H. Du, et al. Overexpression of Stat3C in Pulmonary Epithelium Protects against Hyperoxic Lung Injury J. Immunol., June 1, 2005; 174(11): 7250 - 7256. [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]

				H. M. Wu, M. Jin, and C. B. Marsh Toward functional proteomics of alveolar macrophages Am J Physiol Lung Cell Mol Physiol, April 1, 2005; 288(4): L585 - L595. [Abstract] [Full Text] [PDF]

				U. Lappalainen, J. A. Whitsett, S. E. Wert, J. W. Tichelaar, and K. Bry Interleukin-1{beta} Causes Pulmonary Inflammation, Emphysema, and Airway Remodeling in the Adult Murine Lung Am. J. Respir. Cell Mol. Biol., April 1, 2005; 32(4): 311 - 318. [Abstract] [Full Text] [PDF]

				R. H. Hubner, S. Meffert, U. Mundt, H. Bottcher, S. Freitag, N. E. El Mokhtari, T. Pufe, S. Hirt, U. R. Folsch, and B. Bewig Matrix metalloproteinase-9 in bronchiolitis obliterans syndrome after lung transplantation Eur. Respir. J., March 1, 2005; 25(3): 494 - 501. [Abstract] [Full Text] [PDF]

				D. W. Esson, M. P. Popp, L. Liu, G. S. Schultz, and M. B. Sherwood Microarray Analysis of the Failure of Filtering Blebs in a Rat Model of Glaucoma Filtering Surgery Invest. Ophthalmol. Vis. Sci., December 1, 2004; 45(12): 4450 - 4462. [Abstract] [Full Text] [PDF]

				R. L. Warner, N. W. Lukacs, S. D. Shapiro, N. Bhagarvathula, K. C. Nerusu, J. Varani, and K. J. Johnson Role of Metalloelastase in a Model of Allergic Lung Responses Induced by Cockroach Allergen Am. J. Pathol., December 1, 2004; 165(6): 1921 - 1930. [Abstract] [Full Text] [PDF]

				M. Ochs, L. Knudsen, L. Allen, A. Stumbaugh, S. Levitt, J. R. Nyengaard, and S. Hawgood GM-CSF mediates alveolar epithelial type II cell changes, but not emphysema-like pathology, in SP-D-deficient mice Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1333 - L1341. [Abstract] [Full Text] [PDF]

				M. Jin, J. M. Opalek, C. B. Marsh, and H. M. Wu Proteome Comparison of Alveolar Macrophages with Monocytes Reveals Distinct Protein Characteristics Am. J. Respir. Cell Mol. Biol., September 1, 2004; 31(3): 322 - 329. [Abstract] [Full Text] [PDF]

				J. Elias The Relationship Between Asthma and COPD: Lessons From Transgenic Mice Chest, August 1, 2004; 126(2_suppl_1): 111S - 116S. [Abstract] [Full Text] [PDF]

				V. Lagente, E. Naline, I. Guenon, M. Corbel, E. Boichot, J.-L. Burgaud, P. Del Soldato, and C. Advenier A Nitric Oxide-Releasing Salbutamol Elicits Potent Relaxant and Anti-Inflammatory Activities J. Pharmacol. Exp. Ther., July 1, 2004; 310(1): 367 - 375. [Abstract] [Full Text] [PDF]

				C. A. Owen, Z. Hu, C. Lopez-Otin, and S. D. Shapiro Membrane-Bound Matrix Metalloproteinase-8 on Activated Polymorphonuclear Cells Is a Potent, Tissue Inhibitor of Metalloproteinase-Resistant Collagenase and Serpinase J. Immunol., June 15, 2004; 172(12): 7791 - 7803. [Abstract] [Full Text] [PDF]

				O Prause, S Bozinovski, G P Anderson, and A Linden Increased matrix metalloproteinase-9 concentration and activity after stimulation with interleukin-17 in mouse airways Thorax, April 1, 2004; 59(4): 313 - 317. [Abstract] [Full Text] [PDF]

				X. Lian, C. Yan, L. Yang, Y. Xu, and H. Du Lysosomal acid lipase deficiency causes respiratory inflammation and destruction in the lung Am J Physiol Lung Cell Mol Physiol, April 1, 2004; 286(4): L801 - L807. [Abstract] [Full Text] [PDF]

				S. J. McMillan, J. Kearley, J. D. Campbell, X.-W. Zhu, K. Y. Larbi, J. M. Shipley, R. M. Senior, S. Nourshargh, and C. M. Lloyd Matrix Metalloproteinase-9 Deficiency Results in Enhanced Allergen-Induced Airway Inflammation J. Immunol., February 15, 2004; 172(4): 2586 - 2594. [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]

				C. A. Owen, Z. Hu, B. Barrick, and S. D. Shapiro Inducible Expression of Tissue Inhibitor of Metalloproteinases-Resistant Matrix Metalloproteinase-9 on the Cell Surface of Neutrophils Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): 283 - 294. [Abstract] [Full Text] [PDF]