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Matrix Metalloproteinases in Chronic Obstructive Pulmonary Disease: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Eleni Papakonstantinou.

Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade proteins of the extracellular matrix and the basement membrane. Thus, these enzymes regulate airway remodeling, which is a major pathological feature of chronic obstructive pulmonary disease (COPD). Furthermore, proteolytic destruction in the lungs may lead to loss of elastin and the development of emphysema, which is associated with poor lung function in COPD patients.

  • matrix metalloproteinases
  • chronic obstructive pulmonary disease
  • airway remodelling

1. Introduction

Chronic obstructive pulmonary disease (COPD) is one of the main causes of human mortality globally. It is a chronic inflammatory disease characterized by structural remodeling of the airways and alveolar destruction. Alveolar damage is the result of excessive, uncontrolled and persistent proteolysis, leading to the degradation of selective components of the extracellular matrix (ECM). Several studies have shown that loss of elastin rather than loss of fibrillar collagen due to proteolytic destruction is the cause of the disease and the development of emphysema [52,53,54][1][2][3]. Elastolysis caused by specific matrix metalloproteinases (MMPs) produced by macrophages leads to poor lung function in COPD patients [55,56][4][5].
Cigarette smoke (CS) exposure is the most commonly encountered risk factor for COPD. Chronic smoking is associated with continuous recruitment of inflammatory cells and release of inflammatory mediators, such as MMPs, neutrophil elastase, chemokines, cytokines and reactive oxygen species. Epithelial cells and macrophages activate fibroblasts by releasing mediators, such as TGFβ, leading to airway remodeling. In addition, CS impairs structural cell function and initiates the EMT, a process that leads to endothelial cell dysfunction, which hampers tissue repair and eventually leads to fibrosis [57][6].
The number of macrophages appears to be upregulated in lungs of smokers compared to non-smokers [58][7], while increased macrophage influx has been associated with COPD severity [59][8]. However, the exact role of macrophages in COPD remains elusive due to their functional heterogeneity [60][9]. M1 macrophage phenotype seems rather harmful, contributing to ECM deposition by producing profibrotic cytokines that promote myofibroblast formation [61[10][11],62], while M2 macrophages provide benefits by clearing excess ECM deposition [63][12]. Nonetheless, in long-term inflammatory conditions, such as the causatives of COPD, macrophages promote persistent ECM degradation. For example, macrophages in bronchoalveolar lavage (BAL) of COPD smokers are more prone to degrade elastin than macrophages from healthy individuals due to increased MMP activity [56,64][5][13]. Accordingly, in several studies in humans and mice, MMPs, particularly macrophage-derived MMPs, have been associated with the pathogenesis of COPD. MMPs (Table 1) were shown to promote inflammation and disease progression by influencing macrophage activation rather than acting directly to degrade elastin [56,65][5][14]. The primary role of MMPs is to degrade the ECM; however, they can act on many more substrates than the ECM and have multiple modes of action. Therefore, MMPs can lead to alveolar destruction either by directly degrading the ECM or indirectly by tuning the proteolytic phenotype of macrophages, as may be the role of MMP-10 and MMP-28 [33][15]. Furthermore, MMPs, through their exosites, bind to different macromolecules and are able to control cellular activities without functioning as proteinases, as demonstrated for MMP-12 [33][15].
Regulation of MMP production in COPD may occur at a transcriptional level; it has been shown that several proteins, including early-growth response gene product 1 (EGR1), nuclear factor kappa B (NFκB), globin transcription factor 1 (GATA1), activator protein 1 family members (AP-1) and signal transducer and activator of transcription 3 (STAT3C), affect the MMP gene family. CS extract induced Egr-1 protein expression and increased Egr-1 DNA-binding activity in human lung fibroblasts [66][16]. Treatment with a mixture of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and interferon (IFN)-γ resulted in an increase in the activity of MMP-2 in lung fibroblasts from EGR1 control (+/+) mice but was not detected in that of EGR1 null (−/−) mice, whereas MMP-9 was regulated by EGR1 in a reverse manner [66][16].

2. Collagenases in Chronic OPbstructive Pulmonary Disease

2.1. MMP-1

Matrix metalloproteinase-1 (MMP-1) is a collagenase that degrades collagen, which is significantly associated with COPD [67][17] and is a potential biomarker to better understand the course of COPD in patients [68][18]. Serum and plasma levels of MMP-1 were found to be elevated in COPD patients and correlated with COPD severity, whereas serum MMP-1 levels were found to be significantly elevated in smokers [69][19]. Sputum analysis showed increased MMP-1 levels in both smokers and patients with more advanced COPD [70][20]. In addition, a functional variant of MMP-1, rs1799750 G/GG, was associated with a high risk of COPD [71][21].

2.2. MMP-8

MMP-8 is a metalloendopeptidase localized in neutrophils and macrophages known to be involved in COPD [72][22]. Enhanced levels of MMP-8 were identified in induced sputum of COPD patients [73][23]. In addition, PBMCs and plasma from COPD patients showed high levels of mRNA and protein expression for MMP-8, respectively, and expression was higher during exacerbations compared to steady state, suggesting a role of MMP-8 in COPD [74,75][24][25]. MMP-8 protein, although suppressed, was also detected in exhaled breath condensate of COPD patients, suggesting its association with excessive inflammation [74][24]. In mice deficient in MMP-8, there is increased neutrophilic inflammation in the BAL and peri bronchial region [76][26], whereas serum levels of MMP-8 in patients with atopic COPD were significantly higher than those determined in patients with non-atopic COPD [77][27]. Thus, MMP-8 mediates the inflammatory response by potentially inducing neutrophil apoptosis, making COPD patients more susceptible to acute exacerbation due to the effect of allergens [78][28]. Furthermore, MMP-8 levels were associated with acute dyspnea attacks in patients with atopic COPD, suggesting that MMP-8 may be a potential advisory tool for clinical practice [77][27].

2.3. MMP-13

MMP-13, which is both a collagenase and an elastase, is another critical metalloproteinase in lung destruction during the development of COPD [79][29]. Collagenase-3 levels were found to be upregulated in mice after long-term exposure to cigarette smoke and in patients with COPD [72,80,81][22][30][31]. MMP-13 expression in α1,6-fucosyltransferase-deficient mice and Zntb7 knockout mice was associated with the development of airspace enlargement and therefore with an emphysema-like phenotype [82,83][32][33]. In humans, MMP-13 has been shown to be involved in COPD exacerbations, as its levels remain elevated in smokers after viral infections [84][34]. Furthermore, MMP-13-mediated cleavage of α-1 antitrypsin has been reported to reduce MMP-13 activity and protect against lung damage [85][35]. Therefore, targeting MMP-13 through specific inhibitors or AAT therapies may be beneficial for the treatment of COPD [86][36].

3. Stromalysins in Chronic OPbstructive Pulmonary Disease

3.1. MMP-3

MMP-3 levels have been found to be elevated in patients with COPD, particularly among patients carrying the 6A6A genotype. High levels of MMP-3 are thought to potentially contribute to excessive ECM degradation and worse lung function [87][37]. Interestingly, although smoking has been widely associated with upregulation of MMPs in serum, MMP-3 levels were not found to be elevated in smokers [69][19]. On the other hand, in another study, MMP-3 concentration in BAL was associated with CT markers of small airway disease and appeared to be related to the severity of emphysema [88][38]. Further studies need to be conducted to determine the role of MMP-3 in the pathogenesis of COPD in terms of risk and severity.

3.2. MMP-10

MMP-10 is expressed by macrophages and CD68-positive cells in the lungs and, to a lesser extent, by epithelial cells in response to acute inflammatory conditions [56,89][5][39]. Macrophage-derived MMP-10 mitigates the proinflammatory response by controlling macrophage activation through restraint of M1 polarization and promoting the ability of M2 macrophages to control the expression of gelatinolytic MMPs, particularly MMP-13 [90,91][40][41].
Smoking and tobacco consumption have been shown to affect MMP-10 levels, and MMP-10 has been found to be elevated in the lungs of COPD patients [69][19]. More importantly, its expression is associated with small airway disease and the severity of emphysema [88][38]. Furthermore, MMP-10 in mice appeared to contribute to the development of cigarette-smoke-induced disease by directing macrophage–ECM macrophage remodeling [83][33]. Thus, MMP-10 appears to play an important role within the ECM assembly, suggesting that this proteinase is a relevant target for disease control. However, the lack of a selective inhibitor has prevented researchers from understanding whether targeting MMP-10 is favorable for the treatment of COPD. A potent inhibitor with no obvious zinc-binding moiety was developed that can simultaneously inhibit MMP-10 and MMP-13 [4,92][42][43]. Still, main goal of researchers remains to obtain an inhibitor that selectively inhibits MMP-10 against its close counterparts.

4. Matrilysins in Chronic OPbstructive Pulmonary Disease

MMP-7

MMP-7, or matrilysin, is a potent elastase in humans but not in mice that is expressed by the mucosal epithelium and macrophages in humans but only by epithelial cells in mice [56,93][5][44]. MMP-7 expression has been found to be increased in the blood of COPD patients compared to healthy subjects and is associated with deterioration of lung function [94][45]. In addition, an SNP in the promoter of the MMP-7 gene (rs1156818) is associated with a high risk of COPD [95][46]. In another study, MMP-7 serum levels were reported to be elevated in patients with emphysema and correlated with GOLD stages [67,69][17][19].

5. Gelatinases in Chronic OPbstructive Pulmonary Disease

5.1. MMP-2

Serum levels of MMP-2 (gelatinase A) are significantly elevated in stable COPD patients compared with asthmatic patients and controls, suggesting MMP-2 as a potential biomarker for COPD [96][47]. These data were also confirmed by mass spectrometric analysis of the COPD proteome, where a positive fold change in MMP-2 expression was detected [96][47]. In another study, local expression of MMP-2, as well as MMP-9 and TIMP-1, was associated with pathological changes in the pulmonary interstitium and lung function of COPD patients, suggesting their involvement in COPD progression [97][48]. Although MMP-2 levels are elevated in patients with COPD, the functional role of MMP-2 in COPD has not yet been established. However, it was discovered that MMP-2 expression and activity were significantly increased in lung tissues in humans after injury and in rats with pulmonary fibrosis [98,99][49][50]. Therefore, considering the increased expression of MMP-2 and TIMP-1 in COPD patients and their association with collagen and elastic fiber formation, MMP-2 appears to be involved in ECM remodeling and interstitial fibrosis and to be a suitable therapeutic target for COPD pathogenesis [100][51].

5.2. MMP-9

MMP-9 (gelatinase B) is an elastase expressed in both mice and humans. Although its expression in COPD is increased [101][52], its role remains questionable, mainly due to controversial data on its involvement in COPD. In mice, the absence of MMP-9 did not protect them from developing emphysema in response to LPS-induced inflammation [102][53]. On the other hand, transgenic overexpression of MMP-9 in macrophages led to impulsive emphysema in mice [101][52]. In another transgenic model, MMP-9 deficiency protected against alveolar expansion in response to IL-13-induced inflammation [103][54]. However, MMP-9 may have triggered IL-13-mediated alveolar remodeling. In COPD patients, MMP-9 expression did not vary in different lung compartments, and there was no association either between increased blood MMP-9 expression and progression of emphysema or between MMP-9 mRNA levels in macrophages and markers of ongoing lung injury [104][55]. However, a polymorphism of MMP-9, C1562T, was associated with disease susceptibility in middle-aged and elderly people [105][56].
It was shown that COPD patients are prone to produce higher levels of MMP-9 and MMP-9/TIMP-1 complex than healthy individuals, which is correlated with decreased FEV1% levels in patients with COPD compared to controls [106][57]. Moreover, the levels of MMP-9 and the ratio with TIMP1 have been associated with increased risk of death [107][58]. Increased levels of MMP-9, TIMP-1 and TIMP-2 were also observed in BAL during acute exacerbations of COPD and were negatively correlated with predicted FEV1%, indicating that MMP-9 and TIMPs may be persistent aggravating factors associated with airway remodeling and obstruction, suggesting a pathway connecting frequent exacerbations to lung function decline [108][59]. MMP-9 in COPD is linked to inflammation and lung remodeling, as it uniquely mediates pulmonary inflammation through ECM degradation, neutrophil chemotaxis and augmentation of inflammation. Elevated MMP-9 was independently associated with the risk of acute exacerbations in COPD in two well-characterized COPD cohorts of the SPIROMICS and COPDGene studies, indicating that MMP-9 may serve as a prognostic biomarker and potential therapeutic target in COPD [109][60]. In a recent study, MMP-9 serum levels, along with PGE2 and COX-2 levels, were found to be enhanced in COPD patients relative to healthy subjects and correlated with GOLD grade, CAT score and clinical history [110][61]. Furthermore, MMP-9 could also serve as a therapeutic target in COPD, as novel interventions targeting MMP-9 modulation are being investigated. In human and mouse models, cigarette smoke has been shown to enhance MMP-9 production [111][62] via p38 MAPK/ERK [102][53] and RANKL [112][63], respectively. These findings elucidate the molecular mechanisms involved in MMP-9 induction in COPD and suggest potential new targets for intervention.

6. Membrane-Type Matrix MPetalloproteinases in COPhronic Obstructive Pulmonary Disease

MMP-14

It has been shown that cigarette smoke and tobacco smoke extract (TSE) can promote the secretion of extracellular vehicles (EVs) by both macrophages and bronchial epithelial cells, which contribute to the release of MMP-14 [113][64]. Thus, MMP-14 may be involved in emphysema [114][65]. This view is supported by the increased MMP-14 activity and protein found in the airway epithelium in a mouse model exposed to cigarette smoke [115][66]. However, decreased MMP-14 activity and protein reduce transcripts of mucin 5AC that play an important role in the development of COPD [116][67] Although Mmp14 −/− mice have an emphysema-like phenotype, this was not associated with abnormalities in collagen and elastin deposition or increased inflammation [117][68]. Therefore, the role of MMP-14 in COPD remains unclear.

7. Other Matrix MPetalloproteinases in COPhronic Obstructive Pulmonary Disease

7.1. MMP-12

MMP-12 has been shown to have a proinflammatory function since after its secretion, it is internalized and translocated to the nucleus, leading to enhanced NF-kB signaling [118,119][69][70]. In addition, its non-catalytic C-terminal end has potent antibacterial activity [120][71]. However, the role of these non-proteolytic actions of MMP-12 has not been correlated with COPD. Nevertheless, a number of studies support the involvement of MMP-12 in alveolar destruction and the pathogenesis of COPD, acting either as an elastase or affecting macrophage activation [121][72]. The expression levels of MMP-12 were found to be enhanced in BAL, in peripheral blood mononuclear cells (PBMCs) and in serum from patients with COPD compared to healthy subjects [46[38][73],88], while there is plenty of data supporting that MMP-12 is required for the development of emphysema in mice [122][74]. On the other hand, the presence of single-nucleotide polymorphisms in the promoter of MMP-12, such as the (-82) A/G allele of SNP rs2276109 or Asn357Ser (A/G) of rs652438, has been associated with reduced risk of developing COPD and better prognosis [46][73]. However, other studies have associated these SNPs with severe and very severe COPD (GOLD stages III and IV) [123][75]. In mouse models exposed to cigarette smoke, it has been proposed that macrophage influx is dependent on MMP-12, indicating that MMP-12 acts on elastin degradation [33][15]. This notion is supported by the fact that MMP-12 is required for the generation of a potent macrophage chemoattractant, which is a six-amino-acid fragment of elastin-VGVAPG [124,125][76][77]. On the other hand, it is tempting to hypothesize that this proteinase affects macrophage activation by regulating the proinflammatory activity of macrophages, as well as their ability to express other MMPs that may be implicated in ECM degradation.

7.2. MMP-28

MMP-28, like MMP-10, plays a causative role in cigarette-smoke-induced emphysema [56][5]. The most recently discovered MMP is constitutively expressed in many human and animal tissues in the epithelium, as well as in monocytes and macrophages. In addition, it is expressed in human COPD lung tissue, while cigarette-smoke-exposed mice have been shown to present increased MMP-28 mRNA levels in both alveolar lung tissue and macrophages [126][78]. This suggests a role and contribution of MMP-18 in emphysema. MMP-28 is neither an elastase nor a matrix-degrading proteinase. Nevertheless, MMP-28 influences the inflammatory response by affecting the inflammatory activity of macrophages. In contrast to MMP-10, which promotes a shift in the M1 phenotype to the M2 phenotype of macrophages with subsequent functional changes, MMP-28 is associated with stimulation of chemokine expression [56][5]. Thus, MMP-28 appears to promote the inflammatory response in the pathogenesis of emphysema, although its specific contribution and mode of action remain to be elucidated.

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