American Journal of Respiratory Cell and Molecular Biology

Matrix metalloproteinases (MMPs) (1) represent a family of matrix-degrading proteinases with structural similarities (Figure 1). They require coordination of a zinc ion at the active site for catalysis, and activity is specifically inhibited by the tissue inhibitors of matrix metalloproteinases (TIMPs). There are now nearly 20 MMPs identified that can be loosely subdivided on the basis of their substrate specificity into three collagenases, two gelatinases, three stromelysins, matrilysin, macrophage elastase, and four membrane-type MMPs (MT-MMPs), which are localized to the cell surface. As Gibbs and colleagues report in their articles in this issue (2, 3), macrophages can be an abundant source of MMPs (Table 1).

Table 1. ECM degradation by macrophage-derived MMPs

Interstitial CollagensBasement Membrane ComponentsElastin
Collagenase (MMP-1)III > I > (± II)± LN, EN, PG
Stromelysin (MMP-3)LN, EN, PG, ± PScolIV±
Matrilysin (MMP-7)LN, EN, PG+
Gelatinase B (MMP-9)GLcolIV/V, EN, PG, PS++
Macrophage elastase (MMP-12)LN, EN, PG, PScolIV++++
Membrane type (MT1-MMP or MMP-14)± I > III, IILN, EN, PG

Definition of abbreviations: colIV/V = types IV and V collagen; EN = entactin; GL = gelatin; LN = laminin; PG = proteoglycan; PScolIV = pespsinized type IV collagen. Non-ECM proteins: α1-antitrypsin, α2-macroglobulin, plasminogen to angiostatin, MMP activation, myelin basic protein, serum amyloid protein A, and IL-1β. Shed active: TNF-α, l-selectin, and FGFr. MMPs may also release ECM bound-TGF-β and cleave IGF3BP-releasing IGF-1. This list is inherently incomplete, representing only substrates tested to date. These substrates guide potential biologic functions but the true in vivo substrates are unknown. Adapted from Reference 2. See this reference for complete list of all MMPs and their substrates.

With the exception of neutrophil MMPs (neutrophil collagenase and gelatinase B), which are stored in secondary and tertiary granules poised for rapid release, MMP production and activity are highly regulated. Normal tissues do not store MMPs, and constitutive expression is minimal. MMPs are transcriptionally regulated by growth factors, cytokines, and extracellular matrix (ECM) components. MMPs are secreted as inactive proenzymes, and proteolytic activity is regulated within tissue by zymogen activation and enzyme inhibition. Cell surface localization (either via transmembrane domains or secretion and binding to surface molecules) represents another possible way to spatially control proteolysis. Because MMPs have the capacity to catalyze the degradation of sturdy structural ECM proteins, it has been tempting to speculate that their main role is physiologic tissue remodeling during development, growth, uterine cycling, postpartum involution, and wound repair.

Exuberant or aberrant expression of MMPs can cause tissue damage and has been associated with a variety of destructive diseases, including arthritis, atherosclerotic plaque rupture, aortic aneurysms, and tumor progression. With respect to lung disease, over the past two years over a dozen articles have been published in the American Journal of Respiratory Cell and Molecular Biology and American Journal of Respiratory and Critical Care Medicine regarding MMPs and various lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), cancer, adult respiratory distress syndrome (ARDS), and pleural disease. Attention has focused especially on gelatinase B in asthma and COPD. Asthma is associated with increased gelatinase B in sputum and bronchoalveolar lavage, while alveolar macrophages from patients with COPD were found to have increased collagenase-1 and gelatinase B expression in culture. Gelatinase B expression in bronchial epithelial cells, eosinophils, and mast cells has been investigated, and the role of MMPs in inflammatory cell migration in vitro has been studied. Few studies have addressed a causal role for MMPs in lung injury in vivo. The current studies by Gibbs and colleagues confirm a role for MMPs in vivo and extend the spectrum of MMP involvement to alveolar macrophage-derived MMPs in acute lung injury associated with immune complexes and lipopolysaccharides.

MMPs are believed to play a role in the pathogenesis of acute and chronic destructive diseases through degradation of ECM. Table 1 highlights ECM substrates susceptible to cleavage by MMPs produced by macrophages. Degradation of basement membrane proteins might promote inflammatory cell accumulation and perturbation of epithelial/endothelial architecture, whereas degradation of elastin and perhaps collagen (in the peripheral airspace) could predispose to airspace enlargement characteristic of emphysema.

More interestingly, disruption of ECM may have additional important effects beyond structural instability (4). Cells sense their external environment through their interaction with the ECM. When they are in contact with their appropriate, intact ECM, cells are quiescent (or at least perform their normal functions). However, contact with altered or disrupted ECM triggers a variety of signal transduction pathways, resulting in many cellular responses. For example, degradation of alveolar basement membranes could alter alveolar epithelial cell interaction with ECM components and lead to apoptosis. Such processes have been demonstrated in the involuting mammary gland (5). MMP-mediated ECM fragments have been shown to direct keratinocyte migration during wound repair (6). ECM fragments are also chemotactic for inflammatory cells (7, 8). In fact, we believe that monocyte recruitment to the airspace associated with long-term cigarette smoking may be largely influenced by elastin-derived peptides. In the current studies by Gibbs and associates, MMPs played a role in neutrophil recruitment. While the mechanism is unknown, it might be related to MMP-mediated ECM fragments. Alternatively, MMPs might directly or indirectly influence generation or activation of C-X-C and other neutrophil chemokines.

MMPs also cleave a variety of non-ECM proteins, generating products that have biological consequences. For example, cleavage of α1-antitrypsin will indirectly enhance neutrophil elastase activity as well as directly generate a fragment chemotactic for neutrophils. This fragment may also enhance tumor growth (9). This activity is consistent with the capacity of MMPs to enhance tumorigenesis, tumor angiogenesis, and tumor invasiveness. However, this story becomes more complex because MMP-mediated proteolysis may also inhibit tumor growth. Proteolytic cleavage of plasminogen and, presumably, type XVIII collagen results in the anti-angiogenic fragments angiostatin and endostatin, respectively.

MMPs and closely related ADAMs (A Disintegrin And Metalloproteinase domain) have the capacity to “shed” a variety of bioactive molecules from cell membranes. ADAMs represent a family of cell-membrane–localized proteins also consisting of approximately 20 members to date. About half of the ADAMs contain a metalloproteinase catalytic domain. The molecules proteolytically released from cell surfaces by ADAMs include tumor necrosis factor (TNF)-α, l-selectin, interleukin-6, Fas, TNF receptor, and a variety of other TNF-receptor superfamily members. Additionally, significant stores of ECM-bound transforming growth factor-β (TGF-β) may be proteolytically released by plasmin and perhaps MMPs.

The list of molecules cleaved by MMPs/ADAMs suggests additional functions, including control of cell death, inflammation, infection, and angiogenesis—all of which might be relevant to acute lung injury and repair. How, then, does one determine the biologic function of MMPs? A general approach often taken to determine the role of MMPs (or any protein, for that matter) in health and disease is to (1) find an association between MMP expression and a biologic process or a disease state, (2) generate an animal model that replicates aspects of the human physiologic or pathologic processes, and (3) manipulate expression of the MMP in this model to determine its effect. As in Gibbs and colleagues' studies, MMP activity can be inhibited by use of natural or synthetic inhibitors. Recently, mice have become the model of choice because one can over- or underexpress individual proteins by transgenic and gene-targeting approaches, thus performing highly specific controlled experiments in mammals.

Use of mice with gene-targeted MMPs has recently expanded the role of MMPs to host defense and immunity. With respect to host defense against bacteria: (1) matrilysin-deficient mice fail to process defensins in the gut, resulting in impaired bacterial clearance (Wilson and Parks, unpublished manuscript), and (2) immunocompromised mice lacking macrophage elastase die more readily with bacterial infection (Hartzell and Shapiro, unpublished observations). Gene-targeted mice were also recently used to demonstrate a role for MMPs in an antigen-specific, T-cell– mediated immune response (10). Mice lacking stromelysin-1 failed to develop a normal contact hypersensitivity response to dinitrofluorobenzene (DNFB), whereas gelatinase B–deficient mice developed a normal response to DNFB but failed to resolve the inflammation in a timely manner. These studies raise questions about MMPs in Langerhan cell function and induction of antiinflammatory cytokines such as IL-10.

Of course mice are not humans, and the applicability of MMP studies in mice to human disease depends on the pathogenetic mechanism of the model versus the human disease, and the similarity of proteinase profile between the species. Studies such as the one by Gibbs and associates in this issue, characterizing the rodent macrophage MMP profile, are required to identify similarities and differences between species to ultimately enhance our knowledge of human biology. For example, macrophage elastase is the predominant rodent macrophage MMP, and although it is present in the human macrophages, it may not be as singularly critical. Nevertheless, macrophage elastase–deficient mice provide an excellent model to test the importance of macrophage proteolysis in biology. In vivo studies will be important to convince a critical scientific community of the many emerging and fascinating properties of MMPs.

1. Parks, W. C., and R. P. Mecham, editors. 1998. Matrix Metalloproteinases. Academic Press, San Diego, CA.
2. Gibbs D. F., Warner R. L., Weiss S. J., Johnson K. J., Varani J.Characterization of matrix metalloproteinases produced by rat alveolar macrophages. Am. J. Respir. Cell Mol. Biol.20199911361144
3. Gibbs D. F., Shanley T. P., Warner R. L., Murphy H. S., Varani J., Johnson K. J.Role of matrix metalloproteinases in models of macrophage-dependent acute lung injury: evidence for alveolar macrophage as source of proteinases. Am. J. Respir. Cell Mol. Biol.20199911451154
4. Shapiro S. D.Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Curr. Opin. Cell Biol.101998602608
5. Farrelly N., Lee Y.-J., Oliver J., Dive C., Streuli C. H.Extracellular matrix regulates apoptosis in mammary epithelium through a control on insulin signaling. J. Cell Biol.144199913371347
6. Pilcher B. K., Dumin J. A., Sudbeck B. D., Krane S. M., Welgus H. G., Parks W. C.The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J. Cell Biol.137199714451457
7. Senior R. M., Griffin G. L., Mecham R. P.Chemotactic activity of elastin-derived peptides. J. Clin. Invest.661980859862
8. Hunninghake G. W., Davidson J. M., Rennard S., Szapiel S., Gadek J. E., Crystal R. G.Elastin fragments attract macrophage precursors to diseased sites in pulmonary emphysema. Science2121981925927
9. Kataoka H., Uchino H., Iwamura T., Seiki M., Nabeshima K., Koono M.Enhanced tumor growth and invasiveness in vivo by a carboxyl-terminal fragment of α1-proteinase inhibitor generated by matrix metalloproteinases. Am. J. Pathol.1541999457468
10. Wang, M., X. Qin, J. S. Mudgett, T. A. Ferguson, R. M. Senior, and H. G. Welgus. 1999. Matrix metalloproteinase deficiencies affect contact hypersensitivity: stromelysin-1 deficiency prevents the response and gelatinase B deficiency prolongs the response. Proc. Natl. Acad. Sci. USA (In press)
Address correspondence to: Steven D. Shapiro, M.D., Barnes-Jewish Hospital (North Campus), 216 South Kingshighway, St. Louis, MO 63110. E-mail:

Abbreviations: a disintegrin and metalloproteinase domain, ADAM; chronic obstructive pulmonary disease, COPD; dinitrofluorobenzene, DNFB; extracellular matrix, ECM; lipopolysaccharide, LPS; matrix metalloproteinases, MMPs; membrane-type MMPs, MT-MMPs; tissue inhibitors of matrix metalloproteinases, TIMPs; tumor necrosis factor, TNF.


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