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The Role of Metalloproteinases in the Pathogenesis

of Chronic Obstructive Pulmonary Disease

Rola metaloproteinaz w patogenezie przewlekłej obturacyjnej

choroby płuc

1_{Department of Pulmonary Diseases and Pulmonary Neoplasms, Wroclaw Medical University, Poland} 2 _{Department of Internal Medicine and Allergology, Wroclaw Medical University, Poland}

Adv Clin Exp Med 2009, 18, 3, 303–309 ISSN 1230−025X

REVIEWS

© Copyright by Wroclaw Medical University

Abstract

Chronic obstructive pulmonary disease (COPD) is a tobacco−related lung disease with an excessive and persistent inflammatory response. There is much evidence that the alterations within the extracellular matrix (ECM) evoked by connective tissue cell dysfunctions play a crucial role in the pathogenesis of COPD. Matrix metalloproteinases (MMPs) are believed to play a crucial role in the degradation of almost all extracellular matrix protein components. This effect may be responsible for the complete destruction of the alveolar walls and the formation of abnormal spaces evolving into larger bullae. Tissue inhibitors of metalloproteinases (TIMPs) regulate the synthesis, secre− tion, and activity of MMPs. The decreased secretion of TIMPs in COPD patients can favor increased elastolysis in the lung. The causes of the imbalance between MMPs and TIMPs in COPD are yet not clear. The development of new COPD therapies directed against specific MMPs and TIMPs should be the target of future research (Adv Clin Exp Med 2009, 18, 3, 303–309).

Key words:chronic obstructive pulmonary disease, extracellular matrix, metalloproteinases, tissue inhibitors of metalloproteinases.

Streszczenie

Przewlekła obturacyjna choroba płuc (p.o.ch.p.) jest schorzeniem tytoniozależnym, w którym istotną rolę odgry− wają mechanizmy zapalne. Prowadzą między innymi do zmian składu macierzy pozakomórkowej. Kluczową rolę w tym procesie odgrywają metaloproteinazy macierzy (MMPs – matrix metallproteinases). Jest to grupa enzymów powodująca trawienie niemal wszystkich białek macierzy pozakomórkowej, co prowadzi do zniszczenia ścian pę− cherzyków płucnych i tworzenia dużych pęcherzy rozedmowych. Tkankowe inhibitory metaloproteinaz (TIMPs –

tissue inhibitors of metalloproteinases) regulują syntezę, wydzielanie oraz aktywację MMPs. Zaburzenie równo− wagi MMPs/TIMPs na korzyść MMPs, obserwowane u chorych na p.o.ch.p., może sprzyjać nasileniu procesów elastolizy w płucach. Czynniki zaburzające homeostazę składników macierzy pozakomórkowej nie są dobrze po− znane. Niezbędne są dalsze badania nad nowymi metodami terapii p.o.ch.p. skierowanymi na swoiste białka MMPs i TIMPs (Adv Clin Exp Med 2009, 18, 3, 303–309).

Słowa kluczowe: przewlekła obturacyjna choroba płuc, macierz pozakomórkowa, metaloproteinazy, tkankowy inhibitor metaloproteinaz.

Chronic obstructive pulmonary disease (COPD) is a major and growing global health problem. It ranked as the sixth most common cause of death worldwide in 1990 and the Global Burden of Disease Study predicted that it would become the third most common cause by 2020 [1]. However, COPD has been relatively neglected among com−

inflammatory response appears to be the hallmark of these individuals [3]. This view is supported by numerous studies demonstrating that the severity of COPD and the numbers of various inflammato− ry cells in the lung are strongly correlated [4].

There is much evidence that the alterations within the extracellular matrix (ECM) evoked by connective tissue cell dysfunctions play a crucial role in the pathogenesis of COPD. Especially pul− monary emphysema, the major contributor to mor− bidity and mortality in patients with COPD, is characterized by progressive destruction of the ECM of the lung [5]. This is a result of an imbal− ance between proteinases and endogenous pro− teinase inhibitors that are responsible for the destruction of lung parenchyma. The main cellular sources of enzymatic activity in the lower respira− tory tract are neutrophils and alveolar macrophages, both of which are increased in the smoker’s lung [6]. The increased prevalence of early−onset emphysema in patients with a congen− ital deficiency of α1−antitrypsin, an endogenous

inhibitor of neutrophil elastase (NE), led to the concept of NE as the proteolytic factor in COPD, a hypothesis that has prevailed for nearly 40 years [7]. The evolving concepts of the pathogenesis of COPD, however, have suggested that the involve− ment of other proteinases of different catalytic classes, acting on diverse substrates of ECM com− ponents, is required to promote effective tissue destruction in COPD patients [7]. Evidence from animal studies [8] as well as preliminary studies in humans [9, 10] has suggested that members of the matrix metalloproteinases (MMPs) family are crit− ically involved in the pathogenesis of COPD.

Matrix Metalloproteinases

MMPs are a family of matrix−degrading pro− teinases with structural similarities. In humans they consist of 24 endopeptidases, of which its founding member was first discovered in metamorphosing tail skin of Xenopusin 1961 and its last member, epilysin (MMP28), was discovered some 40 years later [11]. The members of the MMP family can be loosely subdivided on the basis of their substrate specificity into three collagenases, two gelatinases, three stromelysins, matrilysin, macrophage elas− tase, and four membrane−type MMPs (MT−MMPs), which are located on the cell surface [12]. They require the coordination of a zinc ion at the active site for catalysis and their activity is specifically inhibited by the tissue inhibitors of matrix metallo− proteinases (TIMPs) [12].

With the exception of neutrophil MMPs (neu− trophil collagenase and gelatinase B), which are

stored in secondary and tertiary granules and can be released rapidly, MMP production and activity are highly regulated [11]. Normal tissues do not store MMPs and their expression in a healthy con− dition is minimal. MMPs are transcriptionally reg− ulated by growth factors, cytokines, and ECM components. MMPs are secreted as inactive proen− zymes and their proteolytic activity is regulated within tissue by zymogene activation and enzyme inhibition. Cell−surface localization (either via transmembrane domains or secretion and binding to surface molecules) represents another possible way to control proteolysis. Because MMPs have the capacity to catalyze the degradation of sturdy structural ECM proteins, there is speculation that their main role is physiological tissue remodeling during development, growth, uterine cycling, post− partum involution, and wound repair. Excessive or aberrant expression of MMPs can cause tissue damage and has been associated with a variety of destructive diseases, including aortic aneurysm, arthritis, atherosclerotic plaque rupture, and tumor progression. Over the past years, many articles have described the role of MMPs in various lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), cancer, adult respira− tory distress syndrome (ARDS), and pleural dis− ease [13–16].

MMPs are believed to play a role in the patho− genesis of acute and chronic destructive diseases through degradation of the ECM. There are differ− ent ECM substrates susceptible to cleavage by spe− cific MMPs produced by macrophages (Table 1). The degradation of basement membrane proteins might promote inflammatory cell accumulation and damage to the epithelial/endothelial architec− ture, whereas the degradation of elastin and, per− haps, collagen (in the peripheral airspace) could predispose to the airspace enlargement character− istic of emphysema.

chemotactic for inflammatory cells [19, 20]. In fact, monocyte recruitment to the airspace associ− ated with long−term cigarette smoking may be largely influenced by elastin−derived peptides. Gibbs and associates showed that MMPs play an important role in neutrophil recruitment [21]. While the mechanism is unknown, it might be related to MMP−mediated ECM fragments. Alternatively, MMPs might directly or indirectly influence the generation or activation of CXC and other neutrophil chemokines.

Tissue inhibitors of matrix metalloproteinases together with endogenous inhibitors, such as tissue factor pathway inhibitor−2, thrombospondin−1, and

α−2−macroglobulin, play key roles in the MMP inactivation process [13, 27].

MMPs and COPD

Elastin fibers form the mechanical stress−resis− tant structure of the lung by maintaining elasticity and recoil properties. It is not surprising, then, that destruction of these fibers can directly result in a reduction of maximum airflow, one of the physi− ological hallmarks of COPD [22]. There is increas− ing evidence for a role of MMPs in this process.

Chronic exposure to tobacco smoke causes an increased traffic of neutrophils and macrophages in the smoker’s lungs, which in turn are activated and release a number of molecules, including MMPs. Finlay et al. demonstrated for the first time in 1997 the presence of increased levels of matrix metalloproteinases in the lungs of patients with emphysema and suggested that in BAL fluid, col− lagenase activity may be a better indicator of the presence of emphysema than elastase [23]. Interstitial collagenases are involved in fibrillar collagen degradation, cleaving the triple helical

region of collagen types I and III (located in the extracellular matrix of the lung parenchyma) and type II (located in the cartilage of the airways), generating three−fourths and one−fourth collagen fragments [23]. Gelatinases have the capacity to degrade type−IV collagen, the main structural com− ponent of basement membranes [24], and are also able to degrade insoluble elastin [25]. Therefore, excessive collagenase and gelatinase activity may have a profound effect on the major extracellular matrix components of the lungs, provoking inter− stitial fibrillar collagen degradation and contribut− ing to the breakdown of elastic fibers. This effect may be responsible for the complete destruction of the alveolar walls and the formation of abnormal spaces evolving into larger bullae.

There is evidence that in patients with emphyse− ma, MMP−1 (collagenase 1), MMP−2 (gelatinase A), MMP−8 (collagenase 2), MMP−9 (gelatinase B), and MMP−12 (macrophage elastase) play impor− tant roles in COPD pathogenesis [11, 23]. Increases in MMP concentrations can be observed in blood, bronchoalveolar lavage, lung tissue, and induced sputum [11, 23, 26, 27]. All of them have been implicated in tissue destruction in human COPD and emphysema. Immunohistochemical analysis of COPD lungs showed that neutrophils exhibited a positive signal for collagenase 2 and gelatinase B, whereas collagenase 1 and gelatinase A were found mainly in macrophages and epithe− lial cells [26]. MMP−1 expression is increased in the lungs of patients with emphysema, with pre− dominant localization to type II pneumocytes [28]. Mice that specifically express human MMP−9 in their macrophages developed significant signs of lung emphysema [29]. There is an increase in MMP−9 activity in the lung parenchyma of patients with emphysema [9, 30, 31]. Alveolar macrophages from normal smokers express more

Table 1.ECM degradation targets by macrophage−derived MMPs

Tabela 1.Białka macierzy trawione przez pochodzące z makrofagów MMPs

Interstitial collagen Basement membrane Elastin components

Collagenase 1 (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) GL colIV/V, EN, PG, PS ++

Macrophage elastase (MMP−12) – LN, EN, PG, PScolIV ++++

Membrane type (MT1−MMP or MMP−14) +/–I>III,II LN, EN, PG

Abbreviations: colIV/V – collagen types IV and V; EN – entactin; GL – gelatin; LN – laminin; PG – proteoglycan; PScolIV – pepsinized type IV collagen. Adapted from [21].

MMP−9 than those from normal subjects [32], and there is an ever greater increase in cells from patients with COPD [33]. This suggests that these cells, rather than neutrophils, may be the major cellular source of MMP−9 in COPD patients. Russell et al. showed that these alveolar macrophages have greatly enhanced elastolytic activity [34]. In another study he proved this hypothesis using the MMP inhibitor marimastat. It was shown that MMPs account for most of the elastolytic activity released from alveolar macrophages from COPD patients over prolonged periods [34]. MMP−9 and the MMP−9 to TIMP−1 ratio are increased in induced sputum of patients with COPD [35, 36]. Some authors speculate that MMP−9 may be elevated only in severe disease with respiratory failure, but not in mild to severe disease without respiratory failure [37].

MMP−8 and MMP−9 do not only act as secret− ed enzymes, but they are also bound to cells, where they present elastolytic activity. Thus approxi− mately 80% of the MMP−8 and MMP−9 synthe− sized by neutrophils remains associated with the cell surface and is not neutralized by TIMPs, so they may play a critical role in elastolysis [38, 39].

There is evidence that during macrophage influx to the lung, both the number of MMP−12 (macrophage metalloelastase)−expressing macro− phages and the amount of MMP−12 they express, as shown by immunohistochemistry and Western blotting, are higher in BAL samples from COPD patients than in control subjects. In addition, human lung tissue from COPD patients shows a larger number of macrophages expressing MMP− 12 than control subjects [11, 30].

Lim et al. showed that there is direct upregula− tion of MMP−9 and MMP−12 by cigarette smoke in the human lung [32]. However, MMPs can also be upregulated indirectly through the activation of CD147, a known inducer of MMPs. BAL from current and former smokers compared with that of persons who have never smoked shows an increase in CD147 expression. However, there was no positive correlation with emphysema in these studies [40]. In addition, as shown by immunohistochemistry, CD147 expression is found in lung tissue from smokers, where it is localized to bronchiolar epithelium and alveolar macrophages [41].

The interest in MMPs was heightened by the demonstration that emphysema induced by chronic cigarette smoke exposure is prevented in MMP−12–/–

mice [42]. In MMP−12–/– _{mice, emphysema}

induced by IL−13 and IFN overexpression is reduced [43]. Furthermore, there is a marked reduction in the recruitment of monocytes to the lung. This may be because MMPs generate chemo−

tactic peptides that promote macrophage recruit− ment to the parenchyma and airways.

There are some relationships between MMPs and TGF−β. Dallas et al. showed that MMPs acti− vate the latent form of TGF−βto its active form [44]. It is interesting that mice in which the integrin v6 is deleted (Itgb6−null mice) fail to activate TGF−β and develop age−related emphysema, which is pre− vented in MMP−12–/–_{mice and by overexpression}

of TGF−β1 [45]. This suggests that TGF−β1 down− regulates MMP−12 under normal conditions and the absence of TGF−β1 results in excessive MMP− 12 and emphysema. MMP−9–/– _{mice are not pro−}

tected against emphysema induced by cigarette smoke, but they are protected from small−airway fibrosis [46]. MMP−9 activates TGF−β [47]. This process may be mediated via MMP−9−induced pro− teolytic cleavage of latent TGF−β binding pro− tein−1, resulting in the release of TGF−β1 [44]. Therefore, this mechanism could be a link between elastolysis induced by MMP−9 and the simultane− ous production of fibrosis by activation of TGF−

β1. Thus MMP−12 is a prominent MMP in the mouse but, while present in humans, it does not appear to be as important as MMP−9. There is some evidence of various polymorphisms of MMP−1, MMP−9, and MMP−12 that are associated with emphysema [48, 49].

Tissue Inhibitor of Matrix

Metalloproteinases

Four tissue inhibitors of MMPs (TIMP 1–4) counteract MMPs [13]. TIMP−2 and, to a lesser extent, TIMP−1 bind to MMP−9 and inhibit its activity [50]. TIMP−3 binds with high affinity to and inhibits MMP−9 [43]. In contrast to TIMP−2, which is constitutively expressed, TIMP−1, −3, and −4 can be selectively induced by extracellular sig− nals, including growth factors, matrix proteins, and inflammatory cytokines [46]. TIMP−1 has other biological activities as well. It regulates the prolif− eration, apoptosis, and angiogenesis of malignant cells [13]. TIMP−1 has been found in stable asth− ma and diseases connected with excessive fibrosis. For example, increased TIMP−1 level in scleroder− ma correlates with illness severity and lung fibro− sis. TIMP−1 was involved in skin fibroblast prolif− eration, which could contribute to fibrosis in this disease [13]. Increased TIMP−1 level has also been found in viral C hepatitis and correlated with liver fibrosis [13].

stimuli. Pons et al. showed that alveolar macrophages from COPD patients released signif− icantly less TIMP−1 than those from smokers with normal lung function and nonsmokers [53]. Examination of induced sputum reveals that MMP−9 and the MMP−9 to TIMP−1 ratio are increased in patients with COPD [35, 36]. This mechanism favors increased elastolysis in COPD patients [34, 54]. In addition, Hirano et al. showed that the frequency of loss−of−function mutations of TIMP−2 is increased in patients with COPD [55]. Polymorphisms of the TIMP−2 gene have been shown to be associated with the development of COPD in different ethnic populations [56].

The Concepts

of the COPD Treatment

The increasing evidence of the role of MMPs in COPD pathogenesis suggests that either inhibit− ing these proteolytic enzymes or increasing the number of endogenous antiproteases may be ben− eficial and should theoretically prevent the pro−

gression of emphysema [57]. The fact that there are many proteinases implicated in COPD might mean that blocking a single enzyme may not have a major effect. The development of small−mole− cule inhibitors of proteases, particularly those that have elastolytic activity, has produced quite promising results. MMPs can be targets for drug development. A nonselective MMP inhibitor inhibits the development of emphysema in ciga− rette smoke−exposed guinea pigs [58]. However, these nonselective MMP inhibitors, such as mari− mastat, appear to have considerable musculoskele− tal side effects [59]. It is possible that the side effects could be reduced by increasing the selectiv− ity for specific MMPs or by targeting delivery to the lung parenchyma. A dual MMP−9/MMP−12 inhibitor, AZ11557272, can prevent emphysema and small airway thickening in guinea pigs that were exposed to cigarette smoke for six months [60]. Another approach is to reduce the expression of MMPs in pulmonary cells. Treatment of emphyse− ma patients with retinoic acid appears to reduce the concentration of MMP−9 in the circulation [61]. TIMPs may also be used therapeutically, particu− larly if engineered for greater stability [62].

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Address for correspondence:

Paweł Piesiak

Department of Pulmonary Diseases and Pulmonary Neoplasms Grabiszyńska 105

53−439 Wrocław Poland

Tel.: +48 71 334 96 70 E−mail: [email protected]

Conflict of interest: None declared Received: 23.02.2009