Brajesh Singh¹, Koel Chaudhury², Parthasarathi Bhattacharya³

¹Research fellow, School of Medical Science and Technology, ²Associate Professor, School of Medical Science and Technology, Indian Institute of Technology Kharagpur, ³Consultant, Institute of Pulmocare and Research, Kolkata.

Abstract

Chronic obstructive pulmonary disease (COPD), a disease characterized by chronic progressive and poorly reversible airflow limitation in lungs with local and systemic inflammation, is highly prevalent in India with an increasing trend. There is no therapy available so far that addresses the basic pathophysiology of COPD. It is, therefore, imperative to understand the underlying pathogenesis of the disease. A set of proteases known as matrix metalloproteinases (MMPs) are especially involved in the process of alveolar destruction and also in mucus hypersecretion in COPD. The present review summarizes the potential role of key MMPs, which includes MMP-1,-2,-8,-9,-12,-13 and 14 along with inflammatory cytokines and growth factors in the pathogenesis of COPD. Strategies to target these proteases using highly selective inhibitory factors are also discussed. Though the concept seems promising, limited knowledge about the exact functions of a particular MMP in COPD and the complexities of MMP in substrate affinity makes this a challenging task. (The Pulmo -Face, 2014; 14:1, 18-21 )

Address of correspondence: Dr. Koel Chaudhury, Associate Professor, School of Medical Science and Technology, Indian Institute of Technology Kharagpur

ABBREVIATIONS

COPD - Chronic obstructive pulmonary disease;
MMPs - Matrix metalloproteinases;
ECM - Extracellular matrix;
IL - Interleukin;
TNF - Tumor necrosis factor;
TIMPs - Tissue inhibitor of metalloproteinases;
Ig – Immunoglobulin;
TGF - Transforming growth factor;
PDGF - platelet-derived growth factor;
EGF - Epidermal growth factor;
LPS - Lipopolysaccharides;
TACE - TNF-aconverting enzyme;
ERK - Extracellular-signal-regulated kinases;
PAR-1 - Proteinase activated receptor-1;
MAPK - Mitogen activated protein kinase;
SCID - severe combined immunodeficiency disease

INTRODUCTION

COPD, a common respiratory disease, is one of the leading causes of morbidity and mortality among smokers and some non-smokers. It is estimated to be the third leading cause of death by 2020. India contributes a significant and growing percentage of COPD mortality which is estimated to be amongst the highest in the world; crude estimates suggest there are 30 million COPD patients in India. ⁽¹⁾

COPD is characterized by airflow limitation with continuous airway remodeling with or without destruction of alveolar membrane with a persistent inflammatory process. Apart from other factors like exposure to air pollution and occupational dusts and chemicals, smoking is the primary risk factor for COPD that includes chronic bronchitis and emphysema. In emphysema, the peripheral air spaces in the lung are enlarged from destruction of the interalveolar septae and in chronic bronchitis there is hypersecretion of mucus. In both of them there has been remodeling of the airway wall. The chronic inflammation leads to pathological abnormalities in the submucosal glands and surface epithelium to lead to airway mucus hypersecretion in chronic bronchitis. ⁽²⁾

Inflammatory cells, like alveolar macrophages, play an important role in driving the inflammation process in COPD. These cells, associated with different cytokines, participate in the extracellular matrix (ECM) degradation by synthesizing, releasing, and up-regulating several matrix metalloproteinases (MMPs), which contribute to lung injury. This brief review summarizes observations regarding the expression of specific MMPs which play a consistent and important role in the pathogenesis of the disease. Inhibiting MMPs, therefore, appears to be a promising therapeutic strategy.

Matrix metalloproteases (MMPs) in COPD

MMPs are a group of zinc-dependent and calcium dependent endopeptidases that can degrade most of the ECM components, thereby leading to the pathogenesis of COPD. ⁽³⁾ These MMPs, liberated from several cells such as macrophages and neutrophils, are involved in matrix modelling with the destruction of inter-alveolar membrane to form emphysema. ⁽⁴⁾ MMPs are divided into interstitial collagenases, stromelysin, gelatinases, and membrane-type MMPs. Alveolar macrophages are capable of synthesizing MMP-1 (interstitial collagenase 1), MMP-2 (gelatinase A), MMP-9 (gelatinase B), MMP-7 (matrilysin), membrane-type-1 MMP, and MMP-12 (macrophage metalloelastase). The macrophage MMPs are regulated by matrix fragments and by cytokines such as interleukin (IL)-10, IL-13, and tumor necrosis factor (TNF)-α, which keep a balance between the synthesis of MMPs and their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). ⁽⁵⁾ IL-13 is involved in immunoglobulin(Ig)E production by B cells, recruitment of inflammatory cells from the blood to the lung, regulation of MMPs and induction of mucin production and secretion. ^{(6, 7)} There is increasing evidence that smoking causes the activation of MMPs and triggers the pathogenesis in COPD.

MMP-2

MMP-2, an important modulator of cell proliferation, is secreted by both, bronchial epithelial cells and airway smooth muscle cells. Increased immune reactivity for MMP-2 in the lungs of patients with COPD, mainly in alveolar macrophages and airway epithelial cells has been observed. ⁽⁸⁾ Increased MMP-2 activity in mice exposed to long-term cigarette smoke is also reported. MMP-2 mRNA up-regulation and increased protein in lavage and lung tissue has also been identified in emphysema induced by wood smoke. ⁽⁹⁾ In contrast, a study using laser capture micro-dissected samples of human lung parenchyma has shown that MMP-2 gene expression levels decrease with severity of the disease. ⁽⁷⁾

MMP-9

MMP-9 is secreted by bronchial epithelial cells, neutrophils, eosinophils, mast cells and alveolar macrophages. MMP-9 expression is known to be induced by IL-13. ^(10,11) MMP-9 activates latent transforming growth factor beta (TGF-β), which, in turn, has a reciprocal role in activating production and secretion of MMP-9. ⁽¹²⁾ IL-1β and TNF-α inhibit MMP-9 production, although the combination of platelet-derived growth factor (PDGF), IL-1β and TNF-α induces MMP-9 activity. Plasma levels of MMP-9 appear to be increased in α1-antitrypsin deficiency-associated emphysema and in COPD. ⁽¹³⁾ Alveolar macrophages from cigarette smokers are reported to release greater baseline and stimulated amounts of MMP-9. ⁽¹⁴⁾ The authors also observed an increase in MMP-9 protein level in 40% of COPD patients compared to healthy subjects. ⁽¹⁵⁾ MMP-9 is also reported to activate the epidermal growth factor (EGF) which is involved in mucin secretion, thereby contributing to chronic bronchitis in COPD. ⁽¹⁶⁾ Another group of researchers have shown that mucin production induced by acrolein-fog or lipopolysaccharide (LPS) inflammatory stimuli are related to MMP-9 activity. ^{(16, 17)}

MMP-12

MMP-12, a pro-inflammatory substance, itself appears to be a direct cause of matrix degradation. It is known to cause liberation of matrix fragments, which themselves are pro-inflammatory. It is evidenced that exposure to cigarette smoke consistently up regulates MMP-12 production and its release in experimental animals. ^{(18, 19)} TNF-α is normally converted from its membrane-bound pro-form to the released active form by TNF- α converting enzyme (TACE). It is reported that MMP-12 actually functions as a form of TACE, and drives pro-inflammatory reactions by releasing active TNF-α. ⁽²⁰⁾ Several groups are of the opinion that TACE causes mucin production by cleaving the precursor of TGF-α, triggering hypermucus secretion in COPD. ^{(21, 22)} TNF-α over-expressed in mice developed emphysema along with increased gene expression of MMP-12 and a variety of pro-inflammatory chemokines. ⁽²³⁾ There are a few studies which have established the role of MMP-12 in the production of interleukin IL-8^(24-26). A recent study reports release of IL-8 from cultured epithelial cells via pathways involving epidermal growth factor receptor and extracellular-signal-regulated kinase (ERK)1/2 activation. ⁽²⁴⁾ Smoke-evoked neutrophils release elastolytic serine proteases, neutrophil elastase, proteinase 3 and cathepsin. MMP-12 degrades α1-antitrypsin, the major inhibitor of these enzymes, especially of neutrophil elastase. Conversely, neutrophil elastase degrades TIMPs (tissue inhibitors of MMPs) that normally inhibit MMP-12. ⁽²⁷⁾ These findings imply that neutrophil elastase and MMP-12 can interact to amplify the inflammatory response to smoking. Smoke exposure also causes protein leakage from the serum into the alveolar spaces. Among these proteins are plasminogen and prothrombin, which can be converted to plasmin and thrombin; the latter activate proteinase activated receptor-1 (PAR-1) which leads to secretion of the pre-formed MMP-12 protein and its activation. ⁽²⁸⁾

MMP-8 and 13

MMP-8 and MMP-13 are collagenases both sharing collagens I, II and III, and gelatin as substrates. Several studies suggest that MMP-8 can differentiate symptomatic smokers i.e. those who may be at risk of developing COPD ^(29-31) from non-symptomatic chronic smokers. MMP-8 has been identified in induced sputum, ⁽³²⁾ particularly during exacerbations. Further, it is found to be localized to neutrophils and macrophages. ⁽³³⁾ Another group has shown that MMP-8 correlates well with airflow obstruction. ⁽³⁴⁾ There is limited data indicating upregulation of MMP-13 in COPD. No differences have been observed in the expression of MMP-13 gene in human lung parenchyma on comparing different stages of COPD. ⁽²⁹⁾

MMP-1

In the lung, MMP-1 is secreted by the bronchial epithelial cells, type II pneumocytes and alveolar macrophages. In humans, increased levels of MMP-1, localized within the resident alveolar epithelial cells, have been reported in the lungs of patients with emphysema but not in normal controls. ^{(14, 35)} Increased whole lung MMP-1 mRNA and protein have been demonstrated in human and guinea pig emphysema. ⁽³⁵⁾ Cigarette smoke induces MMP-1 expression via the ERK /mitogen activated protein kinase (MAPK) pathway. ⁽²⁰⁾

MMP-14

Zheng et al. have shown that IL-13 causes emphysema via a MMP-and cathepsin-dependent mechanism(s) and have highlighted the common mechanisms that may underlie COPD and asthma. They have demonstrated that emphysema develops when IL-13 induces overexpression of MMP-2, -9, -12, -13, and -14 and cathepsins in the adult murine lung. ⁽³⁶⁾ In another study, Ohnishi et al ⁽³⁷⁾ have reported that MMP-2 and MMP-14 are extensively expressed in emphysematous lung and that elastolytic activity is mainly derived from MMP-2. It is well established that pro-MMP2 is activated by MMP-14 on the cell surface, in the presence of a low concentration of TIMP-2. ⁽³⁸⁾ It is, therefore, speculated that the MMP2/ MMP14/TIMP2 system plays a significant role in MMP mediated degradation of the ECM, ⁽³⁷⁾ which is an established feature in COPD.

Tissue inhibitors of matrix metalloproteases (TIMPs) in COPD

There is strong evidence that TIMP-1 is elevated in smokers and COPD subjects. ^(39-41) Levels of MMP-9 and TIMP-1 assessed in induced sputum of stable COPD patients are reported to be elevated in COPD patients compared to controls. ^{(40, 41)} Nevertheless, the TIMPs have not been considered as therapeutic targets for COPD due to their variation in affinity for different proteases. Though the role of TIMPs in activating pro-MMPs is well accepted, several studies exist which report the MMP-unregulated function of TIMPs, such as inhibition of mitogenic response of human endothelial cells to growth factors and promotion of apoptosis. ^(41-43)

The well-established role of MMPs in various inflammatory, malignant and degenerative diseases promotes the possibility of considering inhibitors of these enzymes as therapeutic candidates for the management of these diseases. Until now disease treatment using MMP inhibitors has been primarily related to cancer and arthritis, where MMPs play a key role in metastasis and cartilage damage, respectively. A dual MMP-9/MMP-12 inhibitor, AZ11557272 has been shown to prevent emphysema and airway thickening in guinea pigs. ⁽⁴⁴⁾ Marimastat, a broad spectrum synthetic inhibitor, has also been reported to inhibit in vivo tumour angiogenesis insevere combined immunodeficiency disease (SCID) and human gastric cancer model of peritoneal dissemination. ⁽⁴⁵⁾ However, Prinomastat, another broad spectrum inhibitor (inhibitor of MMP -2, 3, 9, 13, and 14) did not show improvement in the outcome of chemotherapy in advanced non-small-cell lung cancer. ⁽⁴⁶⁾ One of the MMP inhibitors, AE-941 (Neovastat), an extract from shark cartilage, is shown to inhibit MMPs effectively and is now in Phase III clinical trials for the treatment of metastatic non-small-cell lung cancer. ⁽⁴⁷⁾ A study has reported the efficiency of acetylsalicylic acid in reducing the risk of colon cancer, by directly inhibiting MMP-2 activity. ⁽⁴⁸⁾ A recent study reports the use of highly selective and potent fully human MT1-MMP inhibitory antibody which has markedly slowed tumor progression/metastasis and inhibited angiogenesis in mice with xenogenic human cancer implants. ⁽⁴⁹⁾ Though investigations related to development and use of synthetic MMP inhibitors in various diseases are on the rise, studies on respiratory disorders remain limited.

CONCLUSION

Summarizing, the MMPs appear to play an important role in the airway ECM remodeling in COPD. It appears that many different MMPs are up-regulated in alveolar macrophages, both in humans with emphysema and in cigarette smoke-induced mouse and guinea pig models; and over-expression of some MMPs is significant. Since MMPs possess an active catalytic site and natural in vivo inhibitors, they instantly become attractive therapeutic targets. A wide range of MMP inhibition may be useful for maximal inhibition of ECM degradation. Monoclonal antibodies against MMPs, targeting the substrate of MMPs, can also be exploited to achieve effective MMP inhibition. Combinatorial therapy, such as an MMP inhibitor plus a β2 agonist or low-dose steroids could be another strategy for therapeutic management of the disease.

Despite rigorous scientific effort, discovery of appropriate MMP inhibitor for COPD remains a challenge. It is not easy to develop MMP inhibitors which are highly selective and specific thereby targeting only relevant MMPs. It is crucial to understand the sequential expression and individual contribution of each MMP in the initiation and progression of COPD to allow for the development of a selective and specific target. Moreover, systemic toxicity, lack of correlation between activity of the inhibitor and MMP levels in plasma, and poor efficacy are some of the issues which need attention. Protective immunity and tissue repair should also be a matter of concern while considering MMP inhibitory therapeutic strategy.

REFERENCE

1. Koul P A. Chronic obstructive pulmonary disease: Indian guidelines and the road ahead. Lung India 2013;30:175-7.

2. Markewitz B A, Owens M W, Payne D K. The pathogenesis of chronic obstructive pulmonary disease. Am J Med Sci 1999;318:74-8.

3. Shapiro S D. The macrophage in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:S29-32.

4. Montano M, Beccerril C, Ruiz V, Ramos C, Sansores R H, Gonzalez-Avila G. Matrix metalloproteinases activity in COPD associated with wood smoke. Chest 2004;125:466-72.

5. U.S. Department of Health and Human Services. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General, 2014.

6. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben T Y, Karp C L et al. Interleukin-13: central mediator of allergic asthma. Science 1998;282:2258-61.

7. Wills-Karp M. Interleukin-13 in asthma pathogenesis. Immunol Rev 2004;202:175-90.

8. Gueders M M, Foidart J M, Noel A, Cataldo D D. Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the respiratory tract: potential implications in asthma and other lung diseases. Eur J Pharmacol 2006;533:133-44.

9. Ramos C, Cisneros J, Gonzalez-Avila G, Becerril C, Ruiz Vc, Montaño M. Increase of Matrix Metalloproteinases in Woodsmoke-Induced Lung Emphysema in Guinea Pigs. Inhalation Toxicology 2009;21:119-32.

10. Gosselink J V, Hayashi S, Elliott W M, Xing L, Chan B, Yang L et al. Differential expression of tissue repair genes in the pathogenesis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;181:1329-35.

11. Bailey J R, Bland P W, Tarlton J F, Peters I, Moorghen M, Sylvester P1 et al. IL-13 promotes collagen accumulation in Crohn's disease fibrosis by down-regulation of fibroblast MMP synthesis: a role for innate lymphoid cells? PLoS One 2013;7:e52332.

12. Purwar R, Kraus M, Werfel T, Wittmann M. Modulation of keratinocyte-derived MMP-9 by IL-13: a possible role for the pathogenesis of epidermal inflammation. J Invest Dermatol 2008;128:59-66.

13. Muroski M E, Roycik M D, Newcomer R G, Van den Steen P E, Opdenakker G, Monroe H R et al. Matrix metalloproteinase-9/gelatinase B is a putative therapeutic target of chronic obstructive pulmonary disease and multiple sclerosis. Curr Pharm Biotechnol 2008;9:34-46.

14. Omachi T A, Eisner M D, Rames A, Markovtsova L, Blanc P D. Matrix metalloproteinase-9 predicts pulmonary status declines in alpha1-antitrypsin deficiency. Respir Res 2011;12:35.

15. Segura-Valdez L, Pardo A, Gaxiola M, Uhal B D, Becerril C, Selman Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 2000;117:684-94.

16. Deshmukh H S, Shaver C, Case L M, Dietsch M, Wesselkamper S C, Hardie W D et al. Acrolein-activated matrix metalloproteinase 9 contributes to persistent mucin production. Am J Respir Cell Mol Biol 2008;38:446-54.

17. Binker M G, Binker-Cosen A A, Richards D, Oliver B, Cosen-Binker LI.LPS-stimulated MUC5AC production involves Rac1-dependent MMP-9 secretion and activation in NCI-H292 cells. Biochem Biophys Res Commun 2009;386:124-9.

18. Lim S A M, Roche N, Oliver B G, Mattos W, Barnes P J, Chung K F. Balance of Matrix Metalloprotease-9 and Tissue Inhibitor of Metalloprotease-1 from Alveolar Macrophages in Cigarette Smokers. American Journal of Respiratory and Critical Care Medicine 2000;162:1355-60.

19. Bezerra F S, Valenca S S, Pires K M, Lanzetti M, Pimenta W A, Schmidt A C et al. Long-term exposure to cigarette smoke impairs lung function and increases HMGB-1 expression in mice. Respir Physiol Neurobiol 2011;177:120-6.

20. Xiong Z, Leme A S, Ray P, Shapiro S D, Lee J S. CX3CR1+ lung mononuclear phagocytes spatially confined to the interstitium produce TNF-alpha and IL-6 and promote cigarette smoke-induced emphysema. J Immunol 2011;186:3206-14.

21. Shao M X, Nakanaga T, Nadel J A. Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCI-H292) cells. Am J Physiol Lung Cell Mol Physiol 2004;287:L420-7.

22. Kim S, Lewis C, Nadel J A. CCL20/CCR6 feedback exaggerates epidermal growth factor receptor-dependent MUC5AC mucin production in human airway epithelial (NCI-H292) cells. J Immunol 2011;186:3392-400.

23. Churg A, Wang RD, Tai H, Wang X, Xie C, Dai J et al. Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-alpha release. Am J Respir Crit Care Med 2003;167:1083-9.

24. Fujita M, Shannon JM, Irvin CG, Fagan KA, Cool C, Augustin A et al. Overexpression of tumor necrosis factor-alpha produces an increase in lung volumes and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2001;280:L39-49.

25. Le Quément C1, Guénon I, Gillon JY, Lagente V, Boichot E. MMP-12 induces IL-8/CXCL8 secretion through EGFR and ERK1/2 activation in epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2008;294:L1076-84.

26. Churg A, Zhou S, Wright J L. Series "matrix metalloproteinases in lung health and disease": Matrix metalloproteinases in COPD. Eur Respir J 2012;39:197-209.

27. Nenan S, Planquois J M, Berna P, De Mendez I, Hitier S, Shapiro SD et al. Analysis of the inflammatory response induced by rhMMP-12 catalytic domain instilled in mouse airways . Int Immunopharmacol 2005;5:511-24.

28. Shapiro S D, Goldstein N M, Houghton A M, Kobayashi D K, Kelley D, Belaaouaj A. Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. Am J Pathol 2003;163:2329-35.

29. Raza S L, Nehring L C, Shapiro S D, Cornelius L A. Proteinase-activated receptor-1 regulation of macrophage elastase (MMP-12) secretion by serine proteinases. J Biol Chem 2000;275:41243-50.

30. Pauwels R A, Buist A S, Calverley P M, Jenkins C R, Hurd S S. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. American Journal of Respiratory and Critical Care Medicine 2001;163:1256-76.

31. Willemse B W, ten Hacken N H, Rutgers B, Postma D S, Timens W. Association of current smoking with airway inflammation in chronic obstructive pulmonary disease and asymptomatic smokers. Respir Res 2005;6:38.

32. Stavem K, Sandvik L, Erikssen J. Can global initiative for chronic obstructive lung disease stage 0 provide prognostic information on long-term mortality in men? CHEST Journal 2006;130:318-25.

33. Vernooy J H, Lindeman J H, Jacobs J A, Hanemaaijer R, Wouters E F. Increased activity of matrix metalloproteinase-8 and matrix metalloproteinase-9 in induced sputum from patients with COPD. Chest 2004;126:1802-10.

34. Ilumets H, Rytila P H, Sovijarvi A R, Tervahartiala T, Myllarniemi M, Sorsa T A et al. Transient elevation of neutrophil proteinases in induced sputum during COPD exacerbation. Scand J Clin Lab Invest 2008;68:618-23.

35. Stetler-Stevenson W. The tumor microenvironment: regulation by M M P - i n d e p e n d e n t e f f e c t s o f t i s s u e i n h i b i t o r o f metalloproteinases-2. Cancer and Metastasis Reviews 2008;27:57-66.

36. Zheng T, Zhu Z, Wang Z, Homer RJ, Ma B, Riese RJ, Jr. et al. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema. J Clin Invest 2000;106:1081-93.

37. Ohnishi K, Takagi M, Kurokawa Y, Satomi S, Konttinen Y T. Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. Lab Invest 1998;78:1077-87.

38. Jo Y, Yeon J, Kim H J, Lee S T. Analysis of tissue inhibitor of metalloproteinases-2 effect on pro-matrix metalloproteinase-2 activation by membrane-type 1 matrix metalloproteinase using baculovirus/insect-cell expression system. Biochem J 2000;345 Pt 3:511-9.

39. Imai K, Dalal S S, Chen E S, Downey R, Schulman L L, Ginsburg M et al. Human Collagenase (Matrix Metalloproteinase-1) Expression in the Lungs of Patients with Emphysema. American Journal of Respiratory and Critical Care Medicine 2001;163:786-91.

40. Beeh K M, Beier J, Kornmann O, Buhl R. Sputum matrix metalloproteinase-9, tissue inhibitor of metalloprotinease-1, and their molar ratio in patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and healthy subjects. Respir Med 2003;97:634-9.

41. Owen C A, Hu Z, Barrick B, Shapiro S D. Inducible expression of tissue inhibitor of metalloproteinases-resistant matrix metalloproteinase-9 on the cell surface of neutrophils. Am J Respir Cell Mol Biol 2003;29:283-94.

42. Culpitt S V, Rogers D F, Traves S L, Barnes P J, Donnelly L E. Sputum matrix metalloproteases: comparison between chronic obstructive pulmonary disease and asthma. Respiratory Medicine 2005;99:703-10.

43. Docherty A J, Lyons A, Smith B J, Wright E M, Stephens P E, Harris T J et al. Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature 1985;318:66-9.

44. Churg A, Wang R, Wang X, Onnervik P O, Thim K, Wright J L. Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs. Thorax 2007;62:706-13.

45. Wada N, Otani Y, Kubota T, Kimata M, Minagawa A, Yoshimizu N et al. Reduced angiogenesis in peritoneal dissemination of gastric cancer through gelatinase inhibition. Clin Exp Metastasis 2003;20:431-5.

46. Hande K R, Collier M, Paradiso L, Stuart-Smith J, Dixon M, Clendeninn N et al. Phase I and pharmacokinetic study of prinomastat, a matrix metalloprotease inhibitor. Clin Cancer Res 2004;10:909-15.

47. Falardeau P, Champagne P, Poyet P, Hariton C, Dupont E. Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol 2001;28:620-5.

48. Jiang M C, Liao C F, Lee P H. Aspirin inhibits matrix metalloproteinase-2 activity, increases E-cadherin production, and inhibits in vitro invasion of tumor cells. Biochem Biophys Res Commun 2001;282:671-7.

49. Zucker S, Cao J. Selective matrix metalloproteinase (MMP) inhibitors in cancer therapy: ready for prime time? Cancer Biol Ther 2009;8:2371-3.

Dr. Koel Chaudhury
Associate Professor, School of Medical Science and Technology,
Indian Institute of Technology Kharagpur
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.