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The role of matrix metalloproteinases in cystic fibrosis lung disease.

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  • 1. Dept of Medicine, University of Alabama at Birmingham, Birmingham, AL 35244, USA.
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    • Gaggar A 1
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The European Respiratory Journal, 13 Jan 2011, 38(3):721-727
https://doi.org/10.1183/09031936.00173210 PMID: 21233269 PMCID: PMC4036453

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Abstract 

Significant airway remodelling is a major component of the increased morbidity and mortality observed in cystic fibrosis (CF) patients. These airways feature ongoing leukocytic inflammation and unrelenting bacterial infection. In contrast to acute bacterial pneumonia, CF infection is not cleared efficiently and the ensuing inflammatory response causes tissue damage. This structural damage is mainly a result of free proteolytic activity released by infiltrated neutrophils and macrophages. Major proteases in this disease are serine and matrix metalloproteases (MMPs). While the role of serine proteases, such as elastase, has been characterised in detail, there is emerging evidence that MMPs could play a key role in the pathogenesis of CF lung disease. This review summarises studies linking MMPs with CF lung disease and discusses the potential value of MMPs as future therapeutic targets in CF and other chronic lung diseases.

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Eur Respir J. Author manuscript; available in PMC 2014 May 28.
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The role of matrix metalloproteases in cystic fibrosis lung disease

Amit Gaggar,1,* Andreas Hector,2 Preston E. Bratcher,1 Marcus A. Mall,3 Matthias Griese,2 and Dominik Hartl2
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Abstract

Significant airway remodeling is a major component of the increased morbidity and mortality observed in cystic fibrosis (CF) patients. These airways feature ongoing leukocytic inflammation and unrelenting bacterial infection. In contrast to acute bacterial pneumonia, CF infection is not cleared efficiently and the ensuing inflammatory response causes tissue damage. This structural damage is mainly a result of free proteolytic activity released by infiltrated neutrophils and macrophages. Major proteases in this disease are serine and matrix metalloproteases (MMPs). While the role of serine proteases, such as elastase, has been characterized in detail, there is emerging evidence that MMPs could play a key role in the pathogenesis of CF lung disease. This review summarizes studies linking MMPs with CF lung disease and discusses the potential value of MMPs as future therapeutic targets in CF and other chronic lung diseases.

Keywords: Cystic fibrosis, lung disease, elastase, neutrophil, proteases, antiproteases

Proteolytic activity in cystic fibrosis lung disease

Chronic progressive destruction of the lung is the major cause of death in patients with cystic fibrosis (CF) [1]. While gastrointestinal symptoms are treated efficiently by established medications, such as pancreatic enzyme replacement therapy, the progression of pulmonary symptoms with destruction of pulmonary tissue cannot be controlled sufficiently thus far. CF airways are characterized by airway surface liquid (ASL) depletion producing mucus obstruction and chronic inflammation with persistent leukocyte accumulation, mainly of neutrophils and macrophages. Despite the presence of millions of activated phagocytes, bacterial pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus and Haemophilus influenzae flourish in the CF airway microenvironment, resulting in chronic infection. Since recruited leukocytes are impaired in their antibacterial capacity due to decreased mucociliary clearance [2], CXCR1 receptor cleavage [3], excessive but inefficient neutrophil extracellular trap (NET) formation [4] and other mechanisms, the dehydrated mucus and extracellular DNA obstruct the airways and other toxic products, such as proteases and oxidants, cause host tissue damage. Major proteases in this disease situation are serine and matrix metalloproteases (MMPs). While the role of serine proteases such as neutrophil elastase (NE), cathepsin G and proteinase 3 have been characterized in detail in murine and human studies (including natural and synthetic antagonists), there is emerging evidence that MMPs could play a key role in the pathogenesis of CF lung disease. The amount of free proteolytic activity increases over the lifetime of CF patients [3] and overwhelms the antiprotease shield of the airspaces. These enzymes damage cellular and pulmonary structures, including cilia, elastin, fibronectin, surfactant proteins A and D, immunoglobulins, and CXCR1 on neutrophils and CD4 on lymphocytes [5]. In the following chapters, we will introduce the MMP family and will highlight the potential of several members as future targets in CF lung disease.

MMPs: Structure and function

MMPs are one of four subfamilies within the superfamily of metalloendopeptidases known as the metzincins [6]. There are > 20 MMPs that have been identified and, based on structure and substrate specificity, are divided into different groups. All MMPs exhibit an N-terminal signal sequence, a prodomain region, and active catalytic domain (with a zinc-binding region). Another major domain observed is a hemopexin-like C-terminal domain (found in all MMPs except -7 and -22), which is thought to mediate substrate specificity of the MMP for components of the ECM. Additional domains include a transmembrane domain (found in MMP-14, -15, -16, -24) and GPI anchor (MMP-17 and MMP-25), important to cell-bound MMPs. Furin-recognition motifs are seen in multiple MMP isoform’s prodomain region and type II fibronectin-repeats are seen in gelatinase (MMP-2 and MMP-9) catalytic domains. These regions seem to have important implications to the interaction of the MMP with its substrate (Reviewed in [7]).

MMPs have the combined ability to degrade essentially all connective tissue components. While MMPs are involved in many normal homeostatic mechanisms, they are commonly elevated in their expression and activities in conditions where inflammation and tissue remodeling/repair are operative [8, 9]. MMPs are regulated at various points. They are regulated at the level of transcription (through their induction by various cytokines such as IL-1 and TNF-alpha) and may involve the activation of a diverse group of intracellular signaling cascades (such as p38 MAPK or ERK 1/2 MAPK) leading to activation of nuclear signaling factors such as AP1, NF-kappa B, and STAT to induce MMP transcription [10]. Most MMPs are translated to a zymogen (inactive) form. These enzymes have a pro-domain region which is cleaved through a "cysteine switch" mechanism and is then activated. Activation can be induced by various triggers, including protease-mediated activation (either by another protease or auto-activation by the active form of that MMP), oxidant-mediated activation, or matrix-mediated activation. In addition to regulation of activation, there are numerous inhibitors of MMPs. Although tissue inhibitor of metalloproteases (TIMPs) is often thought of as the predominant group of inhibitors for MMPs, they are really the most specific endogenous MMP inhibitors. Rather, the majority of MMP-related inhibition in vivo occurs through relatively non-specific MMP inhibitors, such as alpha-2 macroglobulin [8, 11]. TIMPs are a group of four small (20-24 kDa) MMP-specific inhibitors which bind to MMPs in a 1:1 stoichiometric relationship [12-15]. Animal studies, in addition to human studies in adults, support a role for MMPs and an imbalance between MMPs and TIMPs in the pathogenesis of several well-recognized pulmonary disorders such as COPD [16, 17] and asthma [18-20].

MMPs perform numerous biologic functions, including degradation of matrix components and remodelling of tissues, release of cytokines, growth factors and chemokines, and modulation of cell mobility and migration [11]. Data suggests that dysregulated cellular production, secretion and activation of MMPs, and/or dysfunction of their inhibitors are involved in pathologic conditions within the lung parenchyma. Through degradation of extracellular matrix components, MMPs can destroy the alveolar epithelium, as well as disrupt reorganization during the repair process [8, 9]. Although previously well-studied in other pulmonary disorders, the role of MMPs in CF lung disease has only recently been emerging and suggests important downstream effects of this proteolytic dysregulation.

MMPs in cystic fibrosis lung disease

MMPs were first found to be upregulated in the airways of CF patients in 1995 when Delacourt et al described the increase of a 95/88 kDa gelatinase isoform (presumably MMP-9) in the sputum of patients with CF lung disease (n=27) compared to asthmatic controls (n=9) with an associated imbalance of TIMP [21]. Since this finding, there has been a burgeoning of MMP literature in CF lung disease, focusing not only on relative protease/antiprotease imbalance, but also increasing evidence for downstream effects of this proteolytic environment. These potential biological effects with regards to CF lung disease are shown in Figure 1.

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Predicted effects of MMPs (depicted as ovals with scissors) activities in the context of cystic fibrosis. A) MMP-2 disrupts chloride current, and inhibition of MMP-2 abrogates this effect. B) MMP-7 functions to repair damage in airway epithelia. C) MMP-8/9 are able to cleave collagen and modify ELR+ CXC chemokines which modulate inflammation in the airways. D) Decreased airway surface liquid (ASL) activates macrophages and increases expression of MMP-12, which cleaves elastin resulting in degradation of the airway and lung parenchyma. These elastin fragments may also increase the recruitment of monocytes and activation of macrophages.

MMP-2

MMP-2 (EC 3.4.24.24) is a protease with gelatinolytic activity (hence its alternate name, Gelatinase A), which is found to be constitutively expressed in various cell types found in the lungs. This enzyme has a broad spectrum of substrates and is involved in modulating diverse cellular functions including angiogenesis [22], tissue remodeling [9], and potentiation of inflammatory response [23]. MMP-2 is activated in a unique MT-MMP dependent manner, demonstrating a classic example of MMP-to-MMP activation [24]. MMP-2 is thought to contribute to the pathogenesis of a variety of pulmonary disorders including COPD, asthma, lung cancer, and interstitial pulmonary fibrosis [25].

MMP-2 has not been extensively studied in CF lung disease but there are some interesting insights into the potential role of this protease in CF. For example, one study has shown that inhibition of MMP-2 in Calu-3 cells (which constitutively express MMP-2) leads to augmentation of chloride transport in these cells, suggesting autocrine regulation of ion transport via this protease [26]. In addition, McElvaney and colleagues have recently demonstrated that NE may augment MMP-2 expression from epithelial cells, potentially leading to increased remodeling and inflammatory response in CF [27]. Interestingly, although MMP-2 elevations have not been consistently observed in pulmonary specimens from individuals with CF [28, 29], a recent manuscript has found that MMP-2 decreases in serum during CF exacerbation [30].

MMP-7

MMP-7 (EC 3.4.24.23), or matrilysin, is the smallest known MMP, but exhibits broad substrate specificity with the capacity to cleave multiple components of the matrix [31]. In addition, MMP-7 has been observed in playing a role in diverse biological responses such as airway re-epithelialization, inflammation [32], host defense [33], and cell growth via cleavage of IGF binding proteins [34]. MMP-7 has been shown to be involved in IPF, as knockout mice are protected from bleomycin-induced injury [35] and MMP-7 is overexpressed in lung tissues from patients with IPF [36].

MMP-7 may play an important role in the injury/repair response in CF lung disease. Dunsmore et al have shown increased MMP-7 expression in the airway epithelia of CF patients, and that it is differentially released either apically or basally from these cells. The authors hypothesize that this regulation is important in the injury response and show that human airways treated with an MMP-7 inhibitor fail to re-epithelialize after injury [37]. To our knowledge, specific studies of the importance of MMP-7 expression in CFTR knockout mice after injury have not yet been published.

MMP-8

MMP-8 (EC 3.4.24.34), or neutrophil collagenase, is one of 3 collagenase MMPs (MMP-1, -8, and -13), and is highly expressed in neutrophils. These collagenases have common cleavage sites for type I, II, and III collagens, producing a three-fourths N-terminal fragment and a one-fourth C-terminal fragment [38-40]. This suggests a potential redundancy for these proteases in disease. MMP-8 has also been show to cleave aggrecan in vitro [41], and may play a role in arthritis [42]. Two specific isoforms of pro-MMP-8 have been described in humans: one which is approximately 80 kDa and is highly expressed in PMNs, and a 55 kDa isoform which is expressed from mesenchymal cells [43]. Beyond the capacity to cleave extracellular matrix, MMP-8 has diverse biological effects including modulation of chemokines [44], regulation of repair response [45], and innate immunity [46]. Increased MMP-8 expression has been characterized in various lung diseases including COPD [47], IPF [43], bronchiectasis [48], and asthma [49].

MMP-8 expression and activity has also been found to be elevated in the airway secretions of patients with CF lung disease [50]. This enzyme is also elevated in the serum of patients with CF, and levels correlate with lung function (MMP-8 level vs. %FEV1, r=-0.468, p<0.001) [30]. Unfortunately, beyond these characterizations, there is little else known regarding the impact of this dysregulation on CF pathogenesis. Recently, a novel neutrophil chemokine (proline-glycine-proline) was found in the sputum of CF patients and MMP-8 was found to be an important enzyme involved in its generation [51]. Further examination of the impact of MMP-8 on progression of CF lung disease is certainly warranted.

MMP-9

Perhaps one of the most extensively-studied proteases, MMP-9 (EC 3.4.24.35), or gelatinase B, is broadly expressed in a variety of cells in the lung including inflammatory (PMNs, macrophages), epithelial, and endothelial cells. This observed redundancy belies important location-specific functions of MMP-9, some of which seem in opposition to other MMP-9 functions. For example, MMP-9 has observed important pro-inflammatory effects by generating PGP [51] and increasing chemokine potency of IL-8 [52], but MMP-9 also belies important role in the regulation of granuloma formation in tuberculosis [53]. Similarly, MMP-9 has been predominately thought to lead to matrix breakdown but recently it has been suggested that MMP-9 may have a role in matrix repair [54, 55].

MMP-9 has been extensively examined in the lower airway secretions of CF patients and has been found to be increased in both quantity and activity [28, 50]. One study found a correlation with lung function (FEV1) and MMP-9 with r value of −0.78 (p = 0.001) [56]. In addition, MMP-9 expression is also elevated in the serum of patients with CF lung disease [30].

MMP-12

MMP-12 (EC 3.4.24.65), also known as macrophage elastase, is a protease secreted by macrophages with the capacity to degrade elastin. MMP-12 was first cloned by Shapiro et al [57] and seems to have partial regulation by proteases such as thrombin and plasmin and can be released from macrophages by a variety of inflammatory cytokines such as TNF-a and IL-1b [58]. This protease has emerging biological effects in modulating cytokine and chemokine networks, including cleavage of pro-TNF-α [59] and ELR+ CXC chemokines [60]. The physiological role of MMP-12-mediated proteolysis remains poorly understood and may be related to remodelling of connective tissue during growth and development, and migration of macrophages into tissues. Interestingly, recent data demonstrated that MMP-12 has direct antimicrobial activity and plays an important role in macrophage-mediated killing of both gram-negative and gram-positive bacteria in the lung and other organs [61]. Increased proteolytic activity of MMP-12 has been shown to play an important role in the pathogenesis of emphysema induced by either cigarette smoke [17] or overexpression of the Th-2 cytokine IL-13 in mice [62].

A recent human study identified an SNP producing a functional variant in the MMP-12 promoter that is associated with lung function in asthmatic children and the risk of COPD in adult smokers, suggesting that MMP-12 plays an important role in the pathogenesis of asthma and COPD [63]. Recently, the expression of MMP-12 in the sputum of CF individuals has been demonstrated [28]. The role of increased MMP-12 activity in CF lung disease has not been studied. However, recent observations in transgenic mice with airway-specific overexpression of the amiloride-sensitive epithelial Na+ channel (βENaC-Tg mice) that exhibit ASL depletion and phenocopy CF lung disease [64] suggest that airway surface dehydration and mucostasis cause macrophage activation and MMP-12-dependent emphysema [65]. Further elucidation of the role of MMP-12 in the human CF lung should be facilitated by the recent development of FRET probes designed to assess MMP-12 activity on leukocytes and biological fluids [66]. Based on their high sensitivity (with a detection limit in the sub-nanomolar range for human MMP-12), these novel MMP-12 FRET sensors should be suitable to measure MMP-12 activity in clinical specimens such as BAL or sputum and determine its role in the pathogenesis and as a potential biomarker of CF and other chronic inflammatory lung diseases.

Outlook: Targeting MMPs to treat cystic fibrosis lung disease

As more information has been found regarding the presence and activity of MMPs in CF lung disease, there has been increased interest in modulating MMP activity to improve disease outcome. Evidence supporting the involvement of MMPs in CF lung disease is summarized in Table 1.

Table 1

IntEnz
Number		Alternative NameMolecular
Weight		Location of
Expression in
Airways		Expression in Cystic
Fibrosis		Predicted Role in Cystic
Fibrosis		References
MMP-2EC 3.4.24.24Gelatinase A72 kDa pro, 64
active		Structural cells
(epithelia,
endothelium) and
macrophages		Detected in BAL fluid,
not detected in sputum,
decreased in serum
during exacerbation		Regulation of ion transport,
increasing remodeling and
inflammatory response		[26], [27], [28],
[29]
MMP-7EC 3.4.24.23Matrilysin28 kDa pro, 19
active		Epithelial cells
predominately		Elevated in airway
epithelia		Possible role in injury/repair[37]
MMP-8EC 3.4.24.34Neutrophil
Collagenase		75 pro, 65 activeNeutrophils and
epithelia		Elevated in serum and
levels are negatively
correlated with lung
function, elevated in
BAL fluid		Modulation of inflammatory
response, airway
remodeling, generation of
bioactive collagen fragments		[30], [50], [51]
MMP-9EC 3.4.24.35Gelatinase B92 pro, 82 activePredominately
neutrophils but also
structural cells
(epithelia,
endothelium) and
macrophages		Elevated in lower
airway secretions and
negatively correlated
with lung function,
elevated in serum		Modulation of inflammatory
response , airway
remodeling, generation of
bioactive collagen fragments		[30], [51], [52],
[56]
MMP-12EC 3.4.24.65Macrophage
Elastase		54 pro, 45 activeMacrophagesDetected in sputum
and serum of CF
patients		Possible role in airway and
parenchymal remodeling,
possible role in generating
bioactive elastin fragments		[28], [30], [65]

MMP inhibition has been extensively studied as a potential therapeutic in cancer, and although there has been significant promise for these drugs, two previous phase III trials have shown no clinical benefit [67]. In addition, an MMP inhibitor (PG-116800) has been studied in post-myocardial infarction cardiac remodelling and has shown no benefit. To date, the clinical use of MMP inhibitors in the setting of inflammatory disorders such as osteoarthritis has been largely disappointing [68]. Unfortunately, many synthetic MMP inhibitors either have been limited from either off-target effects or inability to tolerate side effect profiles. Despite difficulties of translation in other conditions, interest has turned to the potential of MMP inhibition in lung disease such as CF. Various approaches have been entertained for inhibition of these activities and detailed below.

Tissue inhibitors of metalloproteases (TIMPs)

The tissue inhibitors of metalloproteases are naturally occurring inhibitors of MMPs in vivo. While TIMP binding blocks MMP activity, TIMPs themselves can be inactivated by proteases like NE by direct proteolytic degradation [69] or excessive MMP-12 activity [70]. Though this kind of TIMP/MMP dysregulation has been shown to contribute to the pathology of the disease and to correlate to disease severity in animal and human studies, there have not, to our knowledge, been attempts to replete TIMPs as a treatment for CF. Though TIMPs serve as fairly potent inhibitors of MMP activity, the increased quantities of TIMP required to overcome a pro-proteolytic environment would likely make TIMP therapy cost-prohibitive.

Antibiotics

As previously mentioned, the current standard of long term clinical care of patients with CF lung disease often involve 3 times per week dosing of a macrolide antibiotic [71]. While these antibiotics have multiple biological effects, a potent effect is the inhibition of MMP activities. Currently, tetracycline antibiotics have not been systematically examined for similar anti-protease or anti-inflammatory activities in CF. Previous data indicates that tetracyclines have intrinsic anti-inflammatory properties. Doxycycline, a member of the tetracycline family is able to reduce neutrophil chemotaxis [72] and nitric oxide production from murine lung epithelial cells [73]. More pertinently, doxycycline can also inhibit MMP synthesis from human endothelial cells [74]. As MMPs have been well regarded as targets for tetracycline antibiotics in disease [75], there is increasing interest for inhibiting MMPs by these agents. Recent ex vivo data suggests that this class of antibiotic may effectively reduce MMP activity in CF sputum [28]. A single centre randomized-controlled clinical trial is currently planned to examine these effects in an adult inpatient CF population in the United States (Clin Trials.gov #NCT01112059, PI Gaggar).

ACKNOWLEDGEMENTS

Supported by the NIH (HL102371-01A1 to AG), CF Foundation (GAGGAR07A0 to AG), German Research Foundation (DFG MA2081/3-3 and MA 2081/4-1 to M.A.M.) and EC (MEXT-CT-2004-013666 to M.A.M.)

REFERENCES

1. Davis PB. Cystic fibrosis. Pediatr Rev. 2001;22(8):257–264. [Abstract] [Google Scholar]
2. Matsui H, Verghese MW, Kesimer M, Schwab UE, Randell SH, Sheehan JK, Grubb BR, Boucher RC. Reduced three-dimensional motility in dehydrated airway mucus prevents neutrophil capture and killing bacteria on airway epithelial surfaces. J Immunol. 2005;175(2):1090–1099. [Abstract] [Google Scholar]
3. Hartl D, Latzin P, Hordijk P, Marcos V, Rudolph C, Woischnik M, Krauss-Etschmann S, Koller B, Reinhardt D, Roscher AA, Roos D, Griese M. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat Med. 2007;13(12):1423–1430. [Abstract] [Google Scholar]
4. Marcos V, Zhou Z, Yildirim AO, Bohla A, Hector A, Vitkov L, Wiedenbauer EM, Krautgartner WD, Stoiber W, Belohradsky BH, Rieber N, Kormann M, Koller B, Roscher A, Roos D, Griese M, Eickelberg O, Doring G, Mall MA, Hartl D. CXCR2 mediates NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation. Nat Med. 16(9):1018–1023. [Abstract] [Google Scholar]
5. Griese M, Kappler M, Gaggar A, Hartl D. Inhibition of airway proteases in cystic fibrosis lung disease. Eur Respir J. 2008;32(3):783–795. [Abstract] [Google Scholar]
6. Stocker W, Bode W. Structural features of a superfamily of zinc-endopeptidases: the metzincins. Curr Opin Struct Biol. 1995;5(3):383–390. [Abstract] [Google Scholar]
7. Bode W, Maskos K. Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases. Biol Chem. 2003;384(6):863–872. [Abstract] [Google Scholar]
8. Stamenkovic I. Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol. 2003;200(4):448–464. [Abstract] [Google Scholar]
9. Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007;8(3):221–233. [Europe PMC free article] [Abstract] [Google Scholar]
10. Curran S, Murray GI. Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer. 2000;36(13 Spec No):1621–1630. [Abstract] [Google Scholar]
11. Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001;17:463–516. [Europe PMC free article] [Abstract] [Google Scholar]
12. Sato H, Kinoshita T, Takino T, Nakayama K, Seiki M. Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2. FEBS Lett. 1996;393(1):101–104. [Abstract] [Google Scholar]
13. Will H, Atkinson SJ, Butler GS, Smith B, Murphy G. The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by TIMP-2 and TIMP-3. J Biol Chem. 1996;271(29):17119–17123. [Abstract] [Google Scholar]
14. Butler GS, Will H, Atkinson SJ, Murphy G. Membrane-type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases. Eur J Biochem. 1997;244(2):653–657. [Abstract] [Google Scholar]
15. Zucker S, Drews M, Conner C, Foda HD, DeClerck YA, Langley KE, Bahou WF, Docherty AJ, Cao J. Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase 1 (MT1-MMP) J Biol Chem. 1998;273(2):1216–1222. [Abstract] [Google Scholar]
16. Finlay GA, Russell KJ, McMahon KJ, D’Arcy EM, Masterson JB, FitzGerald MX, O’Connor CM. Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients. Thorax. 1997;52(6):502–506. [Europe PMC free article] [Abstract] [Google Scholar]
17. Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science. 1997;277(5334):2002–2004. [Abstract] [Google Scholar]
18. Tanaka H, Miyazaki N, Oashi K, Tanaka S, Ohmichi M, Abe S. Sputum matrix metalloproteinase-9: tissue inhibitor of metalloproteinase-1 ratio in acute asthma. J Allergy Clin Immunol. 2000;105(5):900–905. [Abstract] [Google Scholar]
19. Kelly EA, Busse WW, Jarjour NN. Increased matrix metalloproteinase-9 in the airway after allergen challenge. Am J Respir Crit Care Med. 2000;162(3 Pt 1):1157–1161. [Abstract] [Google Scholar]
20. Hoshino M, Nakamura Y, Sim J, Shimojo J, Isogai S. Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation. J Allergy Clin Immunol. 1998;102(5):783–788. [Abstract] [Google Scholar]
21. Delacourt C, Le Bourgeois M, D’Ortho MP, Doit C, Scheinmann P, Navarro J, Harf A, Hartmann DJ, Lafuma C. Imbalance between 95 kDa type IV collagenase and tissue inhibitor of metalloproteinases in sputum of patients with cystic fibrosis. Am J Respir Crit Care Med. 1995;152(2):765–774. [Abstract] [Google Scholar]
22. Brown MD, Hudlicka O. Modulation of physiological angiogenesis in skeletal muscle by mechanical forces: involvement of VEGF and metalloproteinases. Angiogenesis. 2003;6(1):1–14. [Abstract] [Google Scholar]
23. Kumagai K, Ohno I, Okada S, Ohkawara Y, Suzuki K, Shinya T, Nagase H, Iwata K, Shirato K. Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma. J Immunol. 1999;162(7):4212–4219. [Abstract] [Google Scholar]
24. Ward RV, Atkinson SJ, Slocombe PM, Docherty AJ, Reynolds JJ, Murphy G. Tissue inhibitor of metalloproteinases-2 inhibits the activation of 72 kDa progelatinase by fibroblast membranes. Biochim Biophys Acta. 1991;1079(2):242–246. [Abstract] [Google Scholar]
25. Chakrabarti S, Patel KD. Matrix metalloproteinase-2 (MMP-2) and MMP-9 in pulmonary pathology. Exp Lung Res. 2005;31(6):599–621. [Abstract] [Google Scholar]
26. Duszyk M, Shu Y, Sawicki G, Radomski A, Man SF, Radomski MW. Inhibition of matrix metalloproteinase MMP-2 activates chloride current in human airway epithelial cells. Can J Physiol Pharmacol. 1999;77(7):529–535. [Abstract] [Google Scholar]
27. Geraghty P, Rogan MP, Greene CM, Boxio RM, Poiriert T, O’Mahony M, Belaaouaj A, O’Neill SJ, Taggart CC, McElvaney NG. Neutrophil elastase upregulates cathepsin B and matrix metalloprotease-2 expression. J Immunol. 2007;178(9):5871–5878. [Abstract] [Google Scholar]
28. Gaggar A, Li Y, Weathington N, Winkler M, Kong M, Jackson P, Blalock JE, Clancy JP. Matrix metalloprotease-9 dysregulation in lower airway secretions of cystic fibrosis patients. Am J Physiol Lung Cell Mol Physiol. 2007;293(1):L96–L104. [Abstract] [Google Scholar]
29. Peterson-Carmichael SL, Harris WT, Goel R, Noah TL, Johnson R, Leigh MW, Davis SD. Association of lower airway inflammation with physiologic findings in young children with cystic fibrosis. Pediatr Pulmonol. 2009;44(5):503–511. [Abstract] [Google Scholar]
30. Roderfeld M, Rath T, Schulz R, Seeger W, Tschuschner A, Graf J, Roeb E. Serum matrix metalloproteinases in adult CF patients: Relation to pulmonary exacerbation. J Cyst Fibros. 2009;8(5):338–347. [Abstract] [Google Scholar]
31. Wilson CL, Matrisian LM. Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. Int J Biochem Cell Biol. 1996;28(2):123–136. [Abstract] [Google Scholar]
32. Chen P, Abacherli LE, Nadler ST, Wang Y, Li Q, Parks WC. MMP7 shedding of syndecan-1 facilitates re-epithelialization by affecting alpha(2)beta(1) integrin activation. PLoS One. 2009;4(8):e6565. [Europe PMC free article] [Abstract] [Google Scholar]
33. Wilson CL, Ouellette AJ, Satchell DP, Ayabe T, Lopez-Boado YS, Stratman JL, Hultgren SJ, Matrisian LM, Parks WC. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science. 1999;286(5437):113–117. [Abstract] [Google Scholar]
34. Nakamura M, Miyamoto S, Maeda H, Ishii G, Hasebe T, Chiba T, Asaka M, Ochiai A. Matrix metalloproteinase-7 degrades all insulin-like growth factor binding proteins and facilitates insulin-like growth factor bioavailability. Biochem Biophys Res Commun. 2005;333(3):1011–1016. [Abstract] [Google Scholar]
35. Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, Lollini L, Morris D, Kim Y, DeLustro B, Sheppard D, Pardo A, Selman M, Heller RA. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci U S A. 2002;99(9):6292–6297. [Europe PMC free article] [Abstract] [Google Scholar]
36. Rosas IO, Richards TJ, Konishi K, Zhang Y, Gibson K, Lokshin AE, Lindell KO, Cisneros J, Macdonald SD, Pardo A, Sciurba F, Dauber J, Selman M, Gochuico BR, Kaminski N. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med. 2008;5(4):e93. [Europe PMC free article] [Abstract] [Google Scholar]
37. Dunsmore SE, Saarialho-Kere UK, Roby JD, Wilson CL, Matrisian LM, Welgus HG, Parks WC. Matrilysin expression and function in airway epithelium. J Clin Invest. 1998;102(7):1321–1331. [Europe PMC free article] [Abstract] [Google Scholar]
38. Fields GB. A model for interstitial collagen catabolism by mammalian collagenases. J Theor Biol. 1991;153(4):585–602. [Abstract] [Google Scholar]
39. Williams KE, Olsen DR. Matrix metalloproteinase-1 cleavage site recognition and binding in full-length human type III collagen. Matrix Biol. 2009;28(6):373–379. [Abstract] [Google Scholar]
40. Li DQ, Shang TY, Kim HS, Solomon A, Lokeshwar BL, Pflugfelder SC. Regulated expression of collagenases MMP-1, -8, and -13 and stromelysins MMP-3, -10, and -11 by human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2003;44(7):2928–2936. [Abstract] [Google Scholar]
41. Fosang AJ, Last K, Neame PJ, Murphy G, Knauper V, Tschesche H, Hughes CE, Caterson B, Hardingham TE. Neutrophil collagenase (MMP-8) cleaves at the aggrecanase site E373-A374 in the interglobular domain of cartilage aggrecan. Biochem J. 1994;304(Pt 2):347–351. [Europe PMC free article] [Abstract] [Google Scholar]
42. Fosang AJ, Last K, Maciewicz RA. Aggrecan is degraded by matrix metalloproteinases in human arthritis. Evidence that matrix metalloproteinase and aggrecanase activities can be independent. J Clin Invest. 1996;98(10):2292–2299. [Europe PMC free article] [Abstract] [Google Scholar]
43. Henry MT, McMahon K, Mackarel AJ, Prikk K, Sorsa T, Maisi P, Sepper R, Fitzgerald MX, O’Connor CM. Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF. Eur Respir J. 2002;20(5):1220–1227. [Abstract] [Google Scholar]
44. Van Lint P, Libert C. Matrix metalloproteinase-8: cleavage can be decisive. Cytokine Growth Factor Rev. 2006;17(4):217–223. [Abstract] [Google Scholar]
45. Gutierrez-Fernandez A, Inada M, Balbin M, Fueyo A, Pitiot AS, Astudillo A, Hirose K, Hirata M, Shapiro SD, Noel A, Werb Z, Krane SM, Lopez-Otin C, Puente XS. Increased inflammation delays wound healing in mice deficient in collagenase-2 (MMP-8) FASEB J. 2007;21(10):2580–2591. [Europe PMC free article] [Abstract] [Google Scholar]
46. Lin M, Jackson P, Tester AM, Diaconu E, Overall CM, Blalock JE, Pearlman E. Matrix metalloproteinase-8 facilitates neutrophil migration through the corneal stromal matrix by collagen degradation and production of the chemotactic peptide Pro-Gly-Pro. Am J Pathol. 2008;173(1):144–153. [Europe PMC free article] [Abstract] [Google Scholar]
47. Vernooy JH, Lindeman JH, Jacobs JA, Hanemaaijer R, Wouters EF. Increased activity of matrix metalloproteinase-8 and matrix metalloproteinase-9 in induced sputum from patients with COPD. Chest. 2004;126(6):1802–1810. [Abstract] [Google Scholar]
48. Sepper R, Konttinen YT, Ding Y, Takagi M, Sorsa T. Human neutrophil collagenase (MMP-8), identified in bronchiectasis BAL fluid, correlates with severity of disease. Chest. 1995;107(6):1641–1647. [Abstract] [Google Scholar]
49. Prikk K, Maisi P, Pirila E, Reintam MA, Salo T, Sorsa T, Sepper R. Airway obstruction correlates with collagenase-2 (MMP-8) expression and activation in bronchial asthma. Lab Invest. 2002;82(11):1535–1545. [Abstract] [Google Scholar]
50. Ratjen F, Hartog CM, Paul K, Wermelt J, Braun J. Matrix metalloproteases in BAL fluid of patients with cystic fibrosis and their modulation by treatment with dornase alpha. Thorax. 2002;57(11):930–934. [Europe PMC free article] [Abstract] [Google Scholar]
51. Gaggar A, Jackson PL, Noerager BD, O’Reilly PJ, McQuaid DB, Rowe SM, Clancy JP, Blalock JE. A novel proteolytic cascade generates an extracellular matrix-derived chemoattractant in chronic neutrophilic inflammation. J Immunol. 2008;180(8):5662–5669. [Europe PMC free article] [Abstract] [Google Scholar]
52. Van den Steen PE, Proost P, Wuyts A, Van Damme J, Opdenakker G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact. Blood. 2000;96(8):2673–2681. [Abstract] [Google Scholar]
53. Volkman HE, Pozos TC, Zheng J, Davis JM, Rawls JF, Ramakrishnan L. Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science. 2010;327(5964):466–469. [Europe PMC free article] [Abstract] [Google Scholar]
54. McCawley LJ, O’Brien P, Hudson LG. Epidermal growth factor (EGF)- and scatter factor/hepatocyte growth factor (SF/HGF)- mediated keratinocyte migration is coincident with induction of matrix metalloproteinase (MMP)-9. J Cell Physiol. 1998;176(2):255–265. [Abstract] [Google Scholar]
55. Bove PF, Wesley UV, Greul AK, Hristova M, Dostmann WR, van der Vliet A. Nitric oxide promotes airway epithelial wound repair through enhanced activation of MMP-9. Am J Respir Cell Mol Biol. 2007;36(2):138–146. [Europe PMC free article] [Abstract] [Google Scholar]
56. Sagel SD, Kapsner RK, Osberg I. Induced sputum matrix metalloproteinase-9 correlates with lung function and airway inflammation in children with cystic fibrosis. Pediatr Pulmonol. 2005;39(3):224–232. [Abstract] [Google Scholar]
57. Shapiro SD, Kobayashi DK, Ley TJ. Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. J Biol Chem. 1993;268(32):23824–23829. [Abstract] [Google Scholar]
58. Dasilva AG, Yong VW. Expression and regulation of matrix metalloproteinase-12 in experimental autoimmune encephalomyelitis and by bone marrow derived macrophages in vitro. J Neuroimmunol. 2008;199(1-2):24–34. [Abstract] [Google Scholar]
59. Churg A, Wang RD, Tai H, Wang X, Xie C, Wright JL. Tumor necrosis factor-alpha drives 70% of cigarette smoke-induced emphysema in the mouse. Am J Respir Crit Care Med. 2004;170(5):492–498. [Abstract] [Google Scholar]
60. Dean RA, Cox JH, Bellac CL, Doucet A, Starr AE, Overall CM. Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx. Blood. 2008;112(8):3455–3464. [Abstract] [Google Scholar]
61. Houghton AM, Hartzell WO, Robbins CS, Gomis-Ruth FX, Shapiro SD. Macrophage elastase kills bacteria within murine macrophages. Nature. 2009;460(7255):637–641. [Europe PMC free article] [Abstract] [Google Scholar]
62. Zheng T, Zhu Z, Wang Z, Homer RJ, Ma B, Riese RJ, Jr., Chapman HA, Jr., Shapiro SD, Elias JA. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema. J Clin Invest. 2000;106(9):1081–1093. [Europe PMC free article] [Abstract] [Google Scholar]
63. Hunninghake GM, Cho MH, Tesfaigzi Y, Soto-Quiros ME, Avila L, Lasky-Su J, Stidley C, Melen E, Soderhall C, Hallberg J, Kull I, Kere J, Svartengren M, Pershagen G, Wickman M, Lange C, Demeo DL, Hersh CP, Klanderman BJ, Raby BA, Sparrow D, Shapiro SD, Silverman EK, Litonjua AA, Weiss ST, Celedon JC. MMP12, lung function, and COPD in high-risk populations. N Engl J Med. 2009;361(27):2599–2608. [Europe PMC free article] [Abstract] [Google Scholar]
64. Mall M, Grubb BR, Harkema JR, O’Neal WK, Boucher RC. Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat Med. 2004;10(5):487–493. [Abstract] [Google Scholar]
65. Schubert SC, Trojanek JB, Diemer S, Cobos-Correa A, Zhou Z, Treis D, Dai L, Schatterny J, Hirtz S, Schultz C, Mall MA. Airways surface liquid depletion causes MMP-12 dependent emphysema in βENaC-overexpressing mice [Abstract] J Cyst Fibros. 2009;8:S53. [Google Scholar]
66. Correa A, Trojanek JB, Diemer S, Mall MA, Schultz C. Membrane-bound FRET probe visualizes MMP12 activity in pulmonary inflammation. Nat Chem Biol. 2009;5(9):628–630. [Abstract] [Google Scholar]
67. Dove A. MMP inhibitors: glimmers of hope amidst clinical failures. Nat Med. 2002;8(2):95. [Abstract] [Google Scholar]
68. Krzeski P, Buckland-Wright C, Balint G, Cline GA, Stoner K, Lyon R, Beary J, Aronstein WS, Spector TD. Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double-blind, placebo-controlled study. Arthritis Res Ther. 2007;9(5):R109. [Europe PMC free article] [Abstract] [Google Scholar]
69. Jackson PL, Xu X, Wilson L, Weathington NM, Clancy JP, Blalock JE, Gaggar A. Human neutrophil elastase-mediated cleavage sites of MMP-9 and TIMP-1: implications to cystic fibrosis proteolytic dysfunction. Mol Med. 2010;16(5-6):159–166. [Abstract] [Google Scholar]
70. Shapiro SD, Goldstein NM, Houghton AM, Kobayashi DK, Kelley D, Belaaouaj A. Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. Am J Pathol. 2003;163(6):2329–2335. [Europe PMC free article] [Abstract] [Google Scholar]
71. Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY, Accurso FJ, Campbell PW., 3rd Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290(13):1749–1756. [Abstract] [Google Scholar]
72. Elewski BE, Lamb BA, Sams WM, Jr., Gammon WR. In vivo suppression of neutrophil chemotaxis by systemically and topically administered tetracycline. J Am Acad Dermatol. 1983;8(6):807–812. [Abstract] [Google Scholar]
73. Hoyt JC, Ballering J, Numanami H, Hayden JM, Robbins RA. Doxycycline modulates nitric oxide production in murine lung epithelial cells. J Immunol. 2006;176(1):567–572. [Abstract] [Google Scholar]
74. Hanemaaijer R, Visser H, Koolwijk P, Sorsa T, Salo T, Golub LM, van Hinsbergh VW. Inhibition of MMP synthesis by doxycycline and chemically modified tetracyclines (CMTs) in human endothelial cells. Adv Dent Res. 1998;12(2):114–118. [Abstract] [Google Scholar]
75. Emingil G, Atilla G, Sorsa T, Luoto H, Kirilmaz L, Baylas H. The effect of adjunctive low-dose doxycycline therapy on clinical parameters and gingival crevicular fluid matrix metalloproteinase-8 levels in chronic periodontitis. J Periodontol. 2004;75(1):106–115. [Abstract] [Google Scholar]

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