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Therapeutic Inhibition of Matrix Metalloproteinases for the Treatment of Chronic Obstructive Pulmonary Disease (COPD)
Key words: COPD * Inhibitor * Lung inflammation * Matrix metalloproteinases * Selectivity
ABSTRACT
Background: The incidence of chronic obstructive pulmonary disease (COPD) is increasing worldwide and is ranked as the fourth most common cause of death in the United States. COPD is caused by long-term exposure to cigarette smoke, toxic gases, and particulate matter, leading to airway flow limitation and pulmonary failure. The disease is characterized by an excess of extracellular matrix deposition, increased thickness of airway walls, and destruction of alveolar septae, resulting in reduced functional lung parenchyma and reduced elastic tethering forces to maintain airway patency. Matrix metalloproteinases (MMPs) have been suggested as the major proteolytic enzymes involved in the pathogeneses of COPD because these proteins are a unique family of metalloenzymes that, once activated, can destroy connective tissue. Although several MMP inhibitors have been developed, in vivo specificity and selectivity have slowed the progress.
Scope: This review discusses the structural features of MMPs, their pulmonary cellular sources during the course of the disease, past anti-MMP therapies, and future approaches to inhibiting these proteins for treating COPD patients. Literature searches of PubMed, BioMed, and Medline formed the basis of this analysis and our current understanding of pulmonary changes associated with COPD and the capacity of MMPs to induce a variety of these changes of current biomedical and clinical interest.
Introduction
Chronic obstructive pulmonary disease (COPD) is characterized by a not fully reversible decrease in airway flow (as measured by spirometry) and manifested by a decrease in forced expiratory volume in 1 s (FEV^sub 1^), compared to predicted FEV^sub 1^, and a reduction in the percentage of FEV^sub 1^/FVC (forced vital capacity)1. The chronic cough and sputum production may accompany, and often precede, the decrease in airway flow, although not all individuals with cough and sputum production will develop COPD. Yet a proportion of patients with significant airway flow obstruction display none of these chronic symptoms. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has recently graded the severity of COPD on a scale of O to 4, where grade O corresponds to a risk stage: normal spirometry but chronic cough and sputum production.
Grade 4 corresponds to a very severe stage: FEV^sub 1^/ FVC < 70% and FEV^sub 1^ < 30% of predicted/or chronic respiratory failure2. COPD is both chronic and progressive in nature as pulmonary inflammation plays a major role in lung structural changes. The disease is mainly caused by exposure to cigarette smoke or noxious gases, such as chemicals and air pollutants3, but it is not usually diagnosed until it is clinically apparent and in an advanced stage4. Because only a proportion of individuals exposed to environmental toxins develop the illness, other risk factors, such as shared genetic factors, have also been implicated in the incidence of the disease, and there is an increased risk of COPD within families with COPD probands5. Literature searches of PubMed, BioMed, and Medline formed the basis of this analysis. The papers reviewed included articles in English and French and ranged from approximately 1978 to 2005. Key search terms used included matrix metalloproteinases (MMPs), inhibitor, COPD, selectivity, lung, inflammation, small molecules, and asthma.
At least two different pathological manifestations, each with a distinct structural expression, are included under the term COPD: emphysema and chronic bronchitis.
Emphysema, evidenced by parenchymal damage, displays as destruction of the alveolar septae and a decrease in lung elasticity (Figure 1). One physiological outcome of these structural changes is gas trapping due to the decreased elastic tethering forces required to maintain airway patency during the expiratory phase6. Inspired gas in COPD is always mixed with more dead gas and pulmonary oxygenation is decreased. Bronchitis, on the other hand, is a disease of airways. Hypersecretion and an increase in airway mucus along with epithelial debris could lead to narrowing the airway diameter and obstructing the air passage7.
MMPs have several features that allow them to be candidate proteins involved in the structural changes associated with COPD8. Although the number of MMPs present in healthy lungs is low, parenchymal cells have the capacity to release an array of MMPs upon environmental insults and cytokine stimulation. In addition, inflammatory cells invading the lung during the course of the disease discharge a substantial number of MMPs. From a structural point of view, MMPs have enzymatic activity to digest a range of proteins involved in pulmonary morphology, cell movement, and propagation of pulmonary inflammation9. In this report, the importance of MMPs are evaluated on both structural changes and inflammatory features associated with COPD.
MMPs' structure and their cellular sources
Presently, there are more than 20 MMPs identified that share several common features: signal peptides, prodomain, and catalytic domain, with at least eight of these proteins clustered on chromosome 11 (MMPs -1, -3, -7, -8, -10, -12, -13, and -20), probably due to a gene duplication event10. Classification of MMPs has been difficult because of their substrate, location, and structure specificities; however, they could be at least divided in two groups based on their domain and compartment location: basic secreted (Figure 2a) and membrane anchored (Figure 2b).The majority of the MMPs contain a C-terminal hemopexin-like domain, which is attached by a hinge segment to the rest of the protein. MMPs are synthesized as a proenzyme where the active site of the protein is inactivated through interaction between a Zn^sup 2+^ ion, sequestrated by histidines on the catalytic domain and a cysteine residue on the prodomain fragment.
The proenzyme activation is still not well characterized, but at least two mechanisms have been identified for generation of the active protein: proteolysis cleavage of the prodomain and oxidation of the thiol group of cysteine involved in interaction with the Zn^sup 2+^ ion present on the active site. For example, cleavage of proMMP-2 by MMP-14 would generate an active form of MMP-2(11); and free radicals, mostly generated during inflammatory processes, could activate MMP-2 through oxidation reaction12. Because of the potent bioactivity of MMPs and the potential risk for tissue damage, the MMPs' activity is tightly regulated, because once released out of the cell, the secreted MMPs are restrained by their natural inhibitors known as tissue inhibitor of matrix metalloproteinases (TIMPs), which are present on the extracellular compartment. Several other proteins, such as a2-microglobulin, also have the capacity to inhibit the MMPs' enzymatic activity. As is often seen in complex biological systems, TIMPs are also a family of proteins, with different substrate affinity, that contain four members: TIMPl through TIMP4.
Figure 1. Morphologic alterations of lung structure during pathogenesis of emphysema (b) and chronic bronchitis (d) compared to normal pulmonary acinus (a) and regular bronchi (c), respectively. Tb: terminal bronchiole, Rb: respiratory bronchioles, Ad: alveolar ducts, and As: alveolar sacs. 1 = cartilage plate; 2 = bronchial glands; 3 = thickened and inflamed airway walls; 4 = mucins
Although the healthy adult lung is not a major source of MMPs, parenchymal cells such as airway epithelium, fibroblast, and smooth muscle have the capacity to express active MMPs following stimulation by a variety of agents such as infectious pathogens, environmental toxins, growth factors, and cytokines13-15. Lopez- Boado et al. reported a 25-fold induction of MMP-7 in the lung epithelial cells following infection with Escherichia coli16 and Pseudomonas aeruginosa17, which could explain the upregulation of this enzyme in the airway of cystic fibrosis patients who are commonly infected with these bacteria. It also has been shown that proinflammatory cytokines such as interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-a) upregulate the expression of MMP-9 in human airway epithelial cells following a 1- day treatment18. Additionally, inflammatory cells invading the lung during the course of COPD are also a major source of different MMPs. It has been shown that the neutrophils and macrophages, the predominant inflammatory cells in the lungs of COPD patients, have the capacity to release MMPs -2, -3, -7, -9, and -12(19,20).
MMPs and COPD
Several lines of evidence indicate a possible involvement of MMPs in the pathogenesis of COPD. MMPs have the enzymatic capacity to induce lung morphological changes, which occur during obstructive pulmonary diseases21. Human studies have shown that there is increase in pulmonary expression of MMP -I22, -223 -824, -9(25), - 12(26), and -14(23) in COPD patients. For example, Finlay and colleagues detected collagenase activity in bronchoalveolar lavage fluid (BALF) samples of 100% of emphysematous patients but only in 10% of smoking controls; and MMP-9 was present in 60% of patients compared to 20% in the control group25. Using zymographic analysis, Segura-Valdez et al. showed a sig\nificant upregulation of MMPs -1, - 2, -8, and -9 in BALF obtained from COPD patients compared to control subjects27. In another study, Imai et al. reported detection of MMP-I as mRNA, as revealed by reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization, and protein and enzymatic activity in the lung samples of patients with emphysema but not in the lungs of normal control subjects22.
Additionally, Ohnishi et al. showed a more than 3-fold increase in the level of MMP-2 protein and its activated form, as measured by zymography, in lung samples from emphysematous patients vs. those in the control group23. Another study by Han et al. reported an increase in MMP-9 protein level in 40% of COPD patients compared to healthy subjects, and they also located MMP-9 expression by immunohistochemistry analysis in bronchial epithelium and submucosal areas28. Furthermore, the extracellular MMP inducer, also called basigin and a member of the immunoglobulin G (IgG) superfamily, is increased in smokers' BALF29. Betsuyaku et al. showed that the extracellular MMP inducer was prominent in bronchial gland, bronchial epithelium, and alveolar macrophages. An increase in the level of MMP-9 has been reported in the sputum of patients with chronic bronchitis compared to control subjects30. In addition, acrolein, a component of cigarette smoke, increases mucin 5AC (MUC5AC) in airway epithelial cells by activating the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) cascade31.
Figure 2. Structural domain of MMPs. MMPs could be divided, based on their proteic domains and cellular location, in at least 2 groups: basic secreted (a) and membrane-anchored (b). Both subfamilies contain a signal peptide (SP) a pro, a catalytic, ana a hemopexin-like domain where a zinc ion (Zn^sup 2+^), ligated to three histidines in the catalytic domain, is interacting with a thiol group in the prodomain, keeping MMPs in an inactive form. The membrane-anchored MMPs possess several extra features: a transmembrane (TM), a collagenase like protein, a furin recognition (Fr) domain, and a cytosolic domain (CS). The majority of MMPs share several important features as illustrated in this figure. SP, signal peptide; SH, thiol group; and Zn^sup 2+^, zinc
Inflammatory cells and MMPs
The severity of airway limitation and the rate of decline in pulmonary function has been associated with the severity of airway inflammation in smokers32; and macrophages and neutrophils, which are increased in BALF of smokers with early emphysema24,33, express several MMPS that could be responsible for tissue damage. For example, Finlay et al. isolated macrophages from BALF of patients with emphysema and normal volunteers and assessed them in vitro for MMP expression. Elevated levels of mRNA transcripts for MMP-I and - 9 were detected in macrophages from emphysematous patients vs. those from control subjects, and MMP-9 complexes were secreted by emphysematous patients but not by control subjects34. In addition, cultured airway macrophages from smokers released greater amounts of MMP-9 at baseline and in response to IL-1ß and lipopolysaccharide (LPS) than did those of nonsmokers19. Moreover, Russell et al. reported that macrophages from COPD patients released greater amounts of MMP-9 with greater enzymatic activity than from healthy smokers and nonsmokers35, and cigarette smoke-conditioned culture medium increased MMP-9 from alveolar macrophages of all groups. Additionally, COPD macrophages degraded more elastin than either of the other groups36. In another study, Betsuyaku et al. reported increased neutrophil granule proteins in BALF from subjects with subclinical emphysema, along with an increase in MMP-8 and -9 that the authors reported to be of neutrophilic origin24. Immunohistochemical analysis of COPD lungs by Segura-Valdez et al. revealed an increase in the level of MMP-8 and -9 associated with neutrophils and a rise in the amount of MMP-1, and -2 associated with macrophages and epithelial cells27.
MMP polymorphisms and COPD
Also, genetic mapping has indicated several polymorphisms in MMPs associated with the expression and progression of the disease. Minematsu et al. reported a single nucleotide polymorphism, a significant increase in allelic frequency of the C-1562T in MMP-9, in a Japanese smoker population with emphysema compared to matched smokers without emphysema37. These investigators concluded that the T allele is a risk factor for smoking-induced emphysema, and emphysematous changes were more pronounced in subjects with C/T or T/ T than in those with C/C. In another study, Zhou and colleagues reported that the same polymorphism in MMP-9 is associated with susceptibility to COPD in the Han population of south China38. The authors compared 100 smokers with COPD to 98 healthy smokers with a cigarette consumption equal to, or more than, 20 pack years. However in studies reported by Joos et al., polymorphisms in MMP-I and MMP- 12, but not MMP-9, were identified as being associated with a rate of decline in lung function of 590 continuing smokers who were chosen for having the fastest and slowest 5-year rate of deterioration in pulmonary task39. Furthermore, Hirano et al. reported several polymorphisms of the TIMP-2 gene that were significantly higher in COPD patients compared to control subjects, thereby possibly decreasing the level of TIMP-2 protein in these patient and leading to an increase in pulmonary MMPs40.
The roll of MMPs in murine models of COPD
Experimental studies in mice have also indicated a role for MMPs in the expression of COPD. Transgenic (Tg) mice that overexpressed human MMP-I in their lungs developed emphysema41. In this model, disruption of the alveolar walls and coalescence of the alveolar spaces were not associated with inflammation. A Tg line of mice with the expression of MMP-I as early as 14 days post-conception exhibited morphometric changes by day 5 of age, and the changes in mean linear intercept coincided with an increase in lung compliance42.
Lung specific-IL-13 Tg mice exhibit pulmonary pathology that is comparable to COPD, including alveolar enlargement, lung enlargement, compliance alterations, and respiratory failure43. These Tg mice display a marked increase in the level of MMPs -2, - 9, -12, -13, and -14 in their lungs. However, when IL-13 was overexpressed in the mice deficient in MMP-9 or MMP-12, several pathological features of these animals were noticeably decreased, leading to the notion that IL-13 induces features of COPD by mechanisms partly dependent on MMP-9 and MMP-12. Transgenic mice with inducible overexpression of interferon gamma (IFN-?) in the airways also exhibit emphysema with alveolar enlargement in the presence of macrophageand neutrophil-rich inflammation44. Prominent protease alterations were also noted in IFN-? Tg mice that manifested emphysema, including the induction of MMP-9 and -12. It was proposed that MMPs induce activation of transforming growth factor beta (TG F-ß) and induction of TNF-a and increase collagen synthesis by fibroblasts.
Chronic exposure of mice to cigarette smoke leads to airspace enlargement and alveolar wall destruction. Hautamaki et al. generated MMP-12 deficient mice to determine the contribution of MMP- 12 to the pathogenesis of COPD45. The control mice developed enlarged air spaces, characteristic of emphysema, following a 6- month, 6-day per week exposure to cigarette smoke. However, the MMP- 12 deficient animals were protected from changes in alveolar dimensions. Subsequently, it was reported that MMP-12-mediated emphysema is caused by macrophages releasing TNF-a with preceding endothelial activation, neutrophil influx, and proteolytic matrix breakdown46. Involvement of MMP-12 in the pathogenesis of emphysema was shown in three other mouse models where an increase in bioactive MMP-12 was responsible for the cigarette smoke-induced emphysema47 or generation of spontaneous progressive pulmonary emphysema48, and a significant decrease in the level of protein was protective against the disease49. Although there are multiple examples of involvement of MMPs and animal models of emphysema, there are less data available regarding MMPs and their association with chronic bronchitis in animal models to date.
Figure 3. The cellular sources of MMPs and their biological activities during pathogenesis of COPD. The environmental insults could activate the alveolar macrophages and the airway epithelium to generate several factors, which in turn either directly, or in association with an aerosol insult, induces the release of MMPs from a number of cellular compartments. On the one hand, MMPs can initiate the destruction of the pulmonary architecture and, on the other hand, propagate the inflammatory reactions to sustain the disease progression
Therapeutic intervention of MMPs' inhibition
Because MMPs possess an active catalytic site and natural in vivo inhibitors they become instantly attractive targets for pharmaceutical companies. Two major approaches were undertaken to counterbalance such MMP activity: substrate peptide mimic and small synthetic molecules. Until now disease treatment using MMP inhibitors has been mainly related to cancer and arthritis, where MMPs play a potential role in metastasis and cartilage damage, respectively. For example, tetracyclines, which are used in the treatment of arthritis, have been shown to reduce the activity of MMPs -1, -2 and -9(50). Macpherson et al. developed a nonpeptidic hydroxamic acid inhibitor (CGS 2 702 3A) of the stromelysin group of MMPs, which was orally bioactive and blocked the erosion of cartilage matrix in an in vivo rabbit model of cartilage degradation51.
Batimastat, a broad spectrum MMP inhibitor, showed prolonged survival in an animal model of cancer and some efficacy in phase I clinical trials, but its development was hindere\d by its low bioavailability and limited solubility52. However marimastat, a low- molecular-weight substrate peptide-based hydroximate (inhibitor of MMPs -1, -8, and -13), and prinomastat, based on a sulphonamide- hydroximate scaffold (inhibitor of MMPs -2, -3, and -13), failed at phase III clinical trials of cancer treatment53. Also, development of several other MMP inhibitors was stopped due to the systemic toxicity, lack of correlation between activity of MMP inhibitors and MMP levels in plasma, and poor efficacy54.
Several lessons could be undertaken from the clinical data already available on MMP inhibitors for application to COPD treatment. It is fundamental to know which MMP in the lung is being targeted and the stage of the disease to allow better selectivity and efficacy. The systemic toxicity could potentially be overcome by aerosol delivery of the drug, permitting local administration and a lower dose of medicine. A biological approach, similar to anti-TNF- a treatment of arthritis and anti-immunoglobulin E (IgE) treatment of asthma, could be another avenue to be pursued. Combinational therapy, such as an MMP inhibitor plus a ß2 agonist or low-dose steroids could be another stratagem in managing the disease. Selective downregulation of MMP and upregulation of TIMP, as shown in vitro by all trans-retinoic acid, could be a new therapeutic strategy to modulate the proteinaseiantiproteinase balance in the lung55.
Conclusion
The toxin exposure of the lung leads to a cascade of events leading to a release of mediators that, on the one hand, have the potential to directly damage the pulmonary structures and, on the other hand, to induce inflammatory cell infiltration to maintain and potentiate the disease (Figure 3). MMPs have biological characteristics that allow them to target multiple cells and act on various levels of these inflammatory and destructive processes. Thus, it is crucial to understand the temporal expression and individual contribution of each MMP in the initiation and progression of COPD to allow for development of a selective and specific target. Past experiences have shown that a broad spectrum MMP inhibitor could be of limited benefit. What the consequences of MMP inhibition are on the protective immunity and tissue repair should be a concern to be investigated because these enzymes have natural biological functions related to various substrates and numerous tissues. The drug discovery progress could not only be of benefit for the treatment of COPD but also for other pulmonary diseases such as severe asthma and lung cancer.
Acknowledgement
No grants or industry support funded this work. Editorial support was provided by Ms. Vicki Fisher and Ms. Bonne Cleveland of the Lovelace Respiratory Research Institute, Albuquerque, NM.
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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com
Paper CMRO-2929_5, Accepted for publication: 04 March 2005
Published Online: 29 March 2005
doi: 10.1185/030079905X41417
Massoud Daheshia
Lovelace Respiratory Research Institute and the Department of Pharmacy and Pathology, School of Medicine, University of New Mexico, Albuquerque, NM, USA
Address for correspondence: Dr. Massoud Daheshia, Associate Scientist, Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr. SE, Albuquerque, NM 87108, USA. Tel: 505-348-9618; Fax: 505-348- 8568; email: mdaheshi@LRRI.org
Copyright Librapharm Apr 2005
Source: Current Medical Research and Opinion
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