Matrix metalloproteinases in destructive lung disease

A. McGarry Houghton Divisions of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center and Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle, United States

Correspondence to A. McGarry Houghton: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., D4-100, Seattle, WA 98109, United States. [email protected] Edited by W.C. Parks and S. Apte

Abstract Matrix metalloproteinases (MMPs) play essential physiologic roles in numerous processes ranging from development to wound repair. Unfortunately, given the broad substrate specificity of the MMP family as a whole, aberrant degradation of extracellular matrix proteins can result in destructive disease. Emphysema, the result of destroyed lung elastin and collagen matrix, is the prototypical example of such a destructive process. More recent data has highlighted that MMPs play much more elaborate physiologic and pathophysiologic roles than simple matrix protein cleavage. Key pathophysiological roles for MMPs in emphysema will be discussed herein. © 2015 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (

Introduction The prototypical destructive lung disease is pulmonary emphysema, which is anatomically defined as the permanent enlargement of the peripheral airspaces of the lung distal to the terminal bronchioles [1]. Implicit in this definition is that the permanent airspace enlargement has arisen through the destruction of alveolar wall matrix structures, which is largely accomplished by matrix metalloproteinases (MMPs), and other matrix degrading enzymes [2]. The impact of aberrant MMP function in this regard is not trivial, as chronic obstructive pulmonary disease (COPD), of which emphysema is a major disease component, is currently the 3rd leading cause of death in the United States [3]. (See Fig. 1.) The lung is a sophisticated matrix scaffold on which lung epithelium and endothelium reside [4]. The scaffolding is necessary to create the presence of millions of tiny air sacs, which allow for gas (oxygen and carbon dioxide) exchange. When the wall of an alveolus is destroyed, the air sacs coalesce to form larger ones. These enlarged airspaces empty more slowly, resulting in airflow

obstruction, the hallmark of COPD [5]. The predominating theory regarding the nature of lung matrix destruction in emphysema is the proteinase– anti-proteinase hypothesis [6]. This theory originated from two separate reports—that instillation of elastolytic proteinases into the lungs of laboratory rodents induced emphysema [7]; and that of the five original subjects identified as having a deficiency of the proteinase inhibitor, alpha-one antitrypsin (A1AT), three of them had emphysema [8]. These findings led to the decades long assumption that an imbalance between A1AT and neutrophil elastase (NE) was the cause of cigarette smoke induced emphysema [9,10]. The discovery that MMPs were elaborated by cellular entities within the lung, and capable of degrading essentially all lung matrix components, including elastin, has led to the modification of the original theory [11]. Additionally, it is generally accepted that the proteinase–anti-proteinase hypothesis goes beyond simple matrix degradation, as MMPs perform many other functions that contribute to emphysema formation, including generation and elimination of chemotactic gradients, activation and degradation of other proteinases, and

0022-2836/© 2015 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( Matrix Biol. (2015) 44-46, 167–174


Matrix metalloproteinases in destructive lung disease








IL-17 Th17







Epithelial Cell



IFNg Th1



Monocyte Fig. 1. Schematic of emphysema pathogenesis. Recruitment of inflammatory cells is depicted on the right. Th17 lymphocytes release IL-17, which interacts with its receptor, IL-17RA, on lung epithelial cells, inducing the release of CC and CXC chemokines. The presence of Th1 immunity drives the release of IFNγ inducible chemokines from CD8 + lymphocytes, such as CXCL10. Interaction with CXCR3 on macrophages leads to the release of MMP12. Destruction of lung matrix is depicted on the left. The release of MMP12 generates EFs from elastic fibers, which are chemotactic for monocytes. Similarly, MMP9 activity nicks collagen fibers enabling prolyl endopeptidase to generate PGP, which is chemotactic for neutrophils. Collectively, the release of NE, MMP1, and MMP12 likely accounts for the majority of elastin and collagen degradation in emphysema.

alterations in cellular behavior independent of extracellular matrix [12–16]. These concepts will be discussed herein.

Elastin degradation in emphysema MMP-12 Of all the MMPs, the evidence supporting a role for macrophage elastase (MMP12) in the pathogenesis of emphysema is the strongest. MMP12 is a relatively macrophage specific MMP, of the simple hemopexin domain type. It is not expressed to any large extent at baseline, such that it can only be

identified in quiescent macrophages using electron microscopy, which reveals its sparse presence within intracellular pools [17]. It was initially described as the entity that conferred elastolysis to macrophages, which was later identified as an MMP [18,19]. Mmp12 expression is greatly increased in response to cigarette smoke exposure, due to a number of overlapping mechanisms. Activation of the plasmin/thrombin–proteinase activated receptor (PAR-1) cascade (itself a serine proteinase) leads to the expression of Mmp12, which is inhibitable by A1AT [20]. TGF-β signaling is intimately tied to Mmp12 expression, as αvβ6 integrin deficient mice, incapable of TGF-β1 activation, display enhanced Mmp12 expression and Mmp12 dependent emphysema [21]. An important, though less direct pathway

Matrix metalloproteinases in destructive lung disease

leading to Mmp12 induction, is related to the IFNγ driven Th1 pathway. CD8 + lymphocytes elaborate substantial quantities of the IFNγ responsive chemokines, such as CXCL-9 (Mig), CXCL-10 (IP-10), and CXCL-11 (iTac). These chemokines, particularly CXCL-10, interact with CXCR3 present on macrophages and induce Mmp12 expression [22,23]. Mmp12 is responsible for the ability of macrophages to degrade basement membrane structures both in vitro and in vivo [24]. Interestingly, monocytes do not express Mmp12, and their emigration into tissues is independent of Mmp12 expression. Once emigrated into tissue (such as the lung), differentiated macrophages initiate MMP12 expression, and it is at this time that MMP12 begins to exert its effects. The seminal report establishing MMP12 as a key entity in emphysema pathogenesis came from Hautamaki et al. in 1997, when they observed that Mmp12 −/− mice were resistant to cigarette smoke induced emphysema [25]. Interestingly, Mmp12 −/− mice also failed to accumulate macrophages in the bronchoalveolar lavage (BAL) fluid. This was not responsible for the protection from airspace enlargement, as intratracheal administration of monocyte chemoattractant protein-1 (MCP-1, CCL2) restored the accumulation of macrophages within the lung, but failed to impact chord length (measurement of airspace size). Reduced lung macrophage accumulation in Mmp12 −/− smoke-exposed mice is the result of an absent chemotactic gradient generated by Mmp12 [26]. In fact, there are some reports suggesting that Mmp12 is pro-inflammatory in and of itself, which maps to its catalytic domain [27]. During the course of matrix degradation, Mmp12 generates fragments of elastin (EFs) that take on novel chemotactic properties not afforded to intact elastic fibers [26]. Chemotactic EFs include all of those containing the motifs XGXPG and GXXPG, where X is a hydrophobic amino acid [28,29]. These two motifs are both repeated frequently within the tropoelastin monomer sequence, such that it is difficult to generate EFs that do not possess these chemotactic substances. Antibodies raised against the prototype human EF, VGVAPG, can reduce macrophage accumulation in mouse models of emphysema, which represents a potential therapeutic strategy. The generation of biologically active elastin peptides by MMPs is also discussed in detail in the article on matrikines by Wells et al., Chapter X, in this issue. Alternatively, these same cryptic EF sequences may provide a novel epitope to the immune system [30]. Auto-antibodies against EFs may drive an auto-immune process mediated by CD4 + T cells, which has been proposed to explain the chronic and smoldering disease process, even after smoking cessation. In addition to the above seminal studies of Mmp12 in cigarette smoke induced emphysema, multiple

169 other reports have identified independent factors driving emphysema development, but which do so in an Mmp12 dependent fashion. As mentioned above, αvβ6 −/− mice display diminished TGF-β signaling which results in airspace enlargement independent of cigarette smoke exposure [21]. Having identified high levels of Mmp12 expression by macrophages, the authors were able to abrogate the development of emphysema by crossing the αvβ6 −/− mice to Mmp12-deficient mice. Similarly, CD8-depleted mice display reduced macrophage accumulation and reduced airspace enlargement in response to cigarette smoke, both of which proved to be Mmp12 dependent in this model [22]. More recently, an investigation of IL-17 signaling, known to enhance both CC and CXC chemokine expression from IL-17 receptor (IL-17RA) expressing cells, also concluded that IL17 signaling ultimately contributes to cigarette smoke induced emphysema by promoting macrophage accumulation and Mmp12 expression [31]. Similar findings have also been reported for IL-1β [32] and TNFα transgenics [33], as well as gp91phox (an essential component of NADPH oxidase)-deficient mice [34]. Additional studies of Mmp12 in mouse models of emphysema have uncovered novel roles for the enzyme independent of straightforward matrix destruction and airspace enlargement. Several groups previously identified that MMPs degrade A1AT [35] during the course of cigarette smoke induced emphysema, thereby enhancing the proteolytic activity of NE. Interestingly, NE cleaves and degrades the tissue inhibitors of metalloproteinases (TIMPs), indirectly increasing Mmp12 activity [36]. Thus, these two elastases appear to augment each others function. TNFα is typically membrane bound, and requires sheddase activity by a proteinase to be released and activated. This function has been officially assigned to the TNFα converting enzyme (TACE), otherwise known as ADAM-17 [37]. However, a number of MMPs can perform this activity, including Mmp12. Notably, Mmp12 −/− mice fail to shed TNFα in response to cigarette smoke, which may account for diminished neutrophil recruitment [38]. More recent studies suggest that murine Mmp12 activates CXCL5 (Lix), a neutrophil chemoattractant [39]. Therefore, the absent PMN recruitment observed in Mmp12 −/− mice may be a reflection of this lost activity. Importantly, human MMP12 does not possess this property, but rather degrades a host of neutrophil recruiting CXC chemokines, including CXCL1, − 2, and − 8 [39]. Studies of MMP12 in human COPD/emphysema largely support a role for MMP12 in disease progression, though these results have been nowhere near as unanimous as the murine studies. Expression profiling of alveolar macrophages from non-smokers, smokers, and smokers with COPD has demonstrated that MMP12 is among the most

170 highly expressed genes induced by cigarette smoking [40,41]. Large genetic polymorphism studies have associated a single nucleotide polymorphism (SNP) in MMP12 with COPD prevalence [42]. Another similar study reached a similar conclusion when combined with SNPs in MMP1 [43]. There are other studies that have failed to identify MMP12 expression in alveolar macrophages from emphysematous subjects [44], or to correlate its expression with COPD severity (as measure by GOLD Stage) [45]. Similarly, some cohort studies have failed to associate genetic polymorphisms in MMP12 with COPD prevalence or severity. Based upon the plethora of mouse studies demonstrating an essential role for MMP12 in emphysema, and at least some supportive evidence in human studies, the development of MMP-12 antagonists is underway. A novel MMP9/MMP12 dual inhibitor was shown to effectively prevent cigarette smoke induced airspace enlargement and airway remodeling in a guinea pig model of emphysema [46]. Other, more selective, agents have also been developed [47], and early phase studies in humans have been initiated. However, MMP12 plays two potentially important pro-host functions that should be considered. It appears that the physiologic role for MMP12 is host defense against invading pathogens. Upon engulfment of Gram-positive and Gram-negative bacteria into macrophage phagolysosomes, Mmp12 is rapidly shuttled to the phagolysosome where it can be co-localized with the bacteria. Mmp12 possess bactericidal activity against these organisms, which is mediated by a unique bactericidal motif located within its C-terminal domain, such that these antibacterial properties occur independent of its catalytic properties [48]. Mmp12 has subsequently been shown to play an essential role in the host defense against viral pathogens [49]. Surprisingly, upon viral infection, Mmp12 can be identified within the nucleus of fibroblasts and macrophages, where it functions as a transcription factor, directly causing the induction of interferon-alpha. Given the frequency of both bacterial and viral induced respiratory tract infections in COPD subjects [50], removal of these host defense activities may ultimately prove detrimental. COPD subjects are at very high risk for the development of lung cancer [51–55]. Inhibiting MMP12 in the lungs of smokers may very well prove effective in eliminating ongoing lung matrix destruction, but it may come at a cost of enhanced lung cancer aggressiveness. MMP12 is capable of generating two angiostatic peptides out of matrix precursors [56]. Specifically, Mmp12 generates angiostatin from plasminogen and endostatin from type XVIII collagen. When challenged with tumors, Mmp12 −/− mice fail to generate these peptides, resulting in increased tumor growth and tumor-associated angiogenesis [57,58]. Ultimately, any attempts to antagonize Mmp12 activity within the

Matrix metalloproteinases in destructive lung disease

lungs of smokers should be accompanied with close monitoring for potential lung neoplasms. MMP-9 MMP9, or gelatinase-B, has long been suspected or performing an essential role in COPD/emphysema. MMP9 displays relatively broad substrate specificity including against elastin. The enzyme is rather ubiquitously expressed, including from alveolar macrophages and neutrophils. Notably, neutrophil-derived Mmp9 may be more potent, as it is secreted in a Timp-free fashion [59]. Because of its ubiquitous expression, Mmp9 has been implicated in numerous physiologic and disease processes ranging from development to cancer. Ohnishi et al. illustrated the presence of MMP9 within alveolar macrophages in the setting of COPD that firmly established MMP9 as a leading candidate in the mediation of COPD [60]. There are a number of other supportive studies in humans, though many of these are somewhat dated. The recent body of literature regarding MMP9 in emphysema has proved confusing, to say the least. Despite well-documented elastolytic properties, Mmp9 does not cleave lung elastic fibers during the course of cigarette smoke induced emphysema in mice [61]. Although there may be some subtle differences between the potency of human and murine MMP9, this is unlikely to be the explanation. Accordingly, murine Mmp9 can cleave elastic fibers in vivo, which has clearly been demonstrated in mouse models of abdominal aortic aneurysm (AAA) [62,63]. Atkinson and colleagues undertook a rather elaborate study to examine MMP9 expression from several plugs of human lung tissue, and to correlate its expression with the presence of radiographic emphysema, as evident by CT imaging [61]. However, they were unable to identify any such correlation. There is no question that MMP9 is rather ubiquitously found in the lungs of smokers and smokers with COPD, but it is difficult to assign a causative role in elastic fiber degradation in vivo. That is not to say, however, that MMP9 does not contribute to COPD pathogenesis. Similar to the concept of Mmp12 generated EFs with monocyte chemotactic properties; a novel neutrophil chemoattractant has been described. Prolyl-glycl-prolyl (PGP) tripeptide repeats are abundant within collagen fibers, and once cleaved and released, they display potent neutrophil chemotactic properties [64]. The in vivo generation of PGP repeats during cigarette smoke exposure requires Mmp9 activity to nick the collagen fiber, which then allows the enzyme prolyl endopeptidase to cleave off the PGP repeats [65,66]. Another important role has been described for Mmp9 in the mediation of small airway thickening, which is a major source of airflow obstruction in COPD subjects. Therefore, it is likely that MMP9 contributes to COPD pathogenesis, but


Matrix metalloproteinases in destructive lung disease

unlikely that it does so via direct elastic fiber cleavage. Other elastolytic MMPs Based on simple in vitro assays of catalysis, MMPs − 2, − 3, − 7, and − 10 have all been demonstrated to cleave elastin, though the data is not necessarily convincing for MMPs − 3 and − 10 [12]. There is no question that Mmp2 can degrade elastic fibers in vivo, though the data is most supportive in AAA models [67]. Interestingly, its source in this context is entirely mesenchymal, as bone marrow transplant experiment failed to confer elastolytic capacity to the xenografts recipients [63]. The enzyme has been identified in smoke-exposed bronchial epithelial cells, and there exists some non-correlative data with COPD severity in human subjects [68]. To my knowledge, cigarette smoke exposure in experiments in Mmp2 −/− mice, or in null mutant mice for Mmps − 3, − 7, and − 10, have not been published. MMP7 may contribute to the elastolytic capacity of human alveolar macrophages, though the relevance of this finding remains unclear [69]. Both Mmp7 and Mmp10 are expressed by alveolar macrophages, and may contribute to function of these cells [70]. As such, these MMPs, and other macrophage-derived MMPs, such as Mmp19 [71], may yet emerge as key mediators of emphysema pathogenesis, albeit independent of elastic fiber degradation.

Collagen degradation in emphysema

ma. In reality, it is likely that both are required for the development of clinically relevant disease severity. D'Armiento and colleagues initially reported that MMP1 transgenic mice developed early onset airspace enlargement, in the absence of cigarette smoke [80]. MMP1, or collagenase I, is an interstitial collagenase with robust expression in many pulmonary disorders. There was some debate initially as to whether the phenotype in these MMP1 transgenics represented a developmental abnormality, or if this truly reflected emphysema. Furthermore, as MMP1 isn't expressed in mice, the impact of this study was unclear. Fortunately, additional founders of this line were identified that did not express enhanced MMP1 until after lung development was completed, and these animals still developed airspace enlargement characteristic of emphysema [81]. Enhanced MMP1 expression has also been identified in smoke-exposed guinea pigs, though it is unclear if this enzyme is the counterpart to human MMP1 [82]. Similarly, a murine enzyme, initially termed ColA, but now referred to as Mmp1a, has been cloned and knocked-out. Once again, this enzyme appears to be an interstitial collagenase, but does not display the robust expression as observed for human MMP1. Studies of Mmp1a −/− mice have been limited to cancer models at this time (MMP1a promotes tumor invasion), though controlled studies in emphysema models are likely forthcoming [83]. Studies of MMP1 in humans have been supportive [43]. A SNP in MMP1, in conjunction with a SNP in MMP12, correlates with disease severity in COPD. Enhanced expression of MMP1 by GOLD stage has also been reported [45].


MMP8 and MMP13

Historically, cleavage of elastic fibers was considered the key (and only) event in the development of emphysema. This is based on a few factors. First, the historical evolution of the proteinase–anti-proteinase hypothesis originated thru the study of elastolytic proteinases, specifically [72–74]. Secondly, the fundamental difference between elastic and collagen fibers is that collagen fibrils display self-assembly [75]. Collagen monomers can be secreted into the extracellular space where they self-assemble and become functional collagen fibrils. This means that one can repair injured or degraded collagen. The same does not hold true for elastin. Elastic fiber formation requires the presence of multiple cell types and matrix protein scaffolding that simply does not exist outside of development [76–78]. 14C dating was used to clearly demonstrate that each individual essentially gets one set of elastin for ones lifetime [79], such that elastic fiber degradation in the setting of emphysema is permanent. Despite the above, mounting evidence has supported a role for collagen degradation in emphyse-

MMP8, or neutrophil collagenase, is a neutrophilspecific MMP. Though capable of degrading collagen, it remains unclear if any of its physiologic or pathophysiologic roles involve collagen degradation, and its role in emphysema is unclear. Though upregulated in the lung of smokers, a causative role in COPD has not been clearly established. Mmp8 has been demonstrated to function in a pro-host capacity in cancer, a function that is independent of collagen degradation [84,85]. Similarly, Mmp8 may dampen inflammatory cell recruitment gradients by cleaving certain CXC chemokines [86]. Therefore, Mmp8 could theoretically protect against cigarette smoke induced emphysema. However, it remains unclear if these properties of Mmp8 are important in vivo, as Mmp8 is effectively always in the presence of NE, which possesses all of these same properties, and with much greater potency. MMP13 displays collagenolytic activity against most collagens, including types I, III, and IV [87]. The vast majority of research on Mmp13 has centered upon its role in collagen matrix turnover in developing


Matrix metalloproteinases in destructive lung disease

bone, where it plays essential roles for long bone development [88]. It also appears to assist malignant neoplasms in acquiring an invasive phenotype [89]. Studies regarding a potential role for Mmp13 in collagen degradation in pathogenesis of emphysema are sparse. Despite the existence of Mmp13 −/− mice for quite some time, the role of these mice in cigarette smoke induced emphysema has not been reported.

Summary MMPs substantially contribute to lung matrix degradation during the evolution of cigarette smoke induced emphysema. Degradation of both collagen and elastin matrix proteins are likely required for the development of emphysema, though evidence remains strongest for elastin, especially since adults are effectively incapable of elastic fiber repair. Similarly, degradation components of both collagen and elastin participate in the continual replenishment of neutrophils and macrophages. With respect to possible therapeutic intervention, the evidence is most supportive for MMP12 as unequivocally participating in emphysema pathogenesis. However, given the important contributions of MMP12 to host defense against infectious microorganisms and developing neoplasms, this strategy carries significant potential risk. Received 4 February 2015; Received in revised form 5 February 2015; Accepted 6 February 2015 Available online 14 February 2015 Keywords matrix metalloproteinases; emphysema; elastin

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Matrix metalloproteinases in destructive lung disease

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Matrix metalloproteinases in destructive lung disease.

Matrix metalloproteinases (MMPs) play essential physiologic roles in numerous processes ranging from development to wound repair. Unfortunately, given...
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