Anti-inflammatory properties of MMP inhibitors in experimental models of chronic obstructive pulmonary disease and lung inflammation

  • Catherine le Quément
  • Vincent Lagente
  • Isabelle Guénon
  • Valeria Muzio
  • Jean-Yves Gillon
  • Elisabeth Boichot
Part of the Progress in Inflammation Research book series (PIR)


Matrix metalloproteinases (MMPs) are a group of proteases known to regulate the turnover of extracellular matrix and thus are suggested to be important in the process of lung disease associated with tissue remodelling. Furthermore, the concept that modulation of airway remodelling including excessive proteolysis damage of the tissue, may be of interest as a basis for future treatment. Among the metalloproteinases (MMPs) family, macrophage elastase (MMP-12) is able to degrade extracellular matrix components such as elastin and is involved in tissue remodelling processes in chronic obstructive pulmonary disease including emphysema. Recent studies using broad spectrum MMP or dual MMP-9/MMP-12 inhibitors have demonstrated a reduction in both inflammatory process and airspace enlargement in lung tissue. In the present chapter, we also report the inhibitory activity of a new MMP-9/MMP-12 inhibitor, AS112108, on acute lung inflammatory processes induced by cigarette smoke.


Chronic Obstructive Pulmonary Disease Cigarette Smoke Chronic Obstructive Pulmonary Disease Patient Respir Crit Cigarette Smoke Exposure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Pauwels R (2000) COPD: the scope of the problem in Europe. Chest 117: 332S–335SPubMedCrossRefGoogle Scholar
  2. 2.
    Saetta M (1999) Airway inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 160: S17–20PubMedGoogle Scholar
  3. 3.
    Eidelman D, Saetta MP, Ghezzo H, Wang NS, Hoidal JR, King M, Cosio MG (1990) Cellularity of the alveolar walls in smokers and its relation to alveolar destruction. Functional implications. Am Rev Respir Dis 141: 1547–1552PubMedGoogle Scholar
  4. 4.
    Finkelstein R, Fraser RS, Ghezzo H, Cosio MG (1995) Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med 152: 1666–1672PubMedGoogle Scholar
  5. 5.
    Tetley TD (2002) Macrophages and the pathogenesis of COPD. Chest 121: 156S–159SPubMedCrossRefGoogle Scholar
  6. 6.
    Finlay GA, O’Driscoll LR, Russell KJ, D’Arcy EM, Masterson JB, FitzGerald MX, O’Connor CM (1997). Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Respir Crit Care Med 156: 240–247PubMedGoogle Scholar
  7. 7.
    Shapiro SD, Senior RM (1999). Matrix metalloproteinases. Matrix degradation and more. Am J Respir Cell Mol Biol 20: 1100–1102PubMedGoogle Scholar
  8. 8.
    Shipley JM, Doyle GA, Fliszar CJ, Ye QZ, Johnson LL, Shapiro SD, Welgus HG, Senior RM (1996) The structural basis for the elastolytic activity of the 92-kDa and 72-kDa gelatinases. Role of the fibronectin type II-like repeats. J Biol Chem 271: 4335–4341PubMedCrossRefGoogle Scholar
  9. 9.
    Vu T,_ Werb Z (1998). Gelatinase B: structure, regulation, and function. In: WC Parks, RP Mecham (eds): Matrix Metalloproteinases. Academic Press, San Diego, 115–148CrossRefGoogle Scholar
  10. 10.
    Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA, Opdenakker G (2002) Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9). Crit Rev Biochem Mol Biol 37: 375–536PubMedCrossRefGoogle Scholar
  11. 11.
    Ohnishi K, Takagi M, Kurokawa Y, Satomi S, Konttinen YT (1998) Matrix metalloproteinase-mediated extracellular matrix protein degradation in human pulmonary emphysema. Lab Invest 78: 1077–1087PubMedGoogle Scholar
  12. 12.
    Kang MJ, Oh YM, Lee JC, Kim DG, Park MJ, Lee MG, Hyun IG, Han SK, Shim YS, Jung KS (2003) Lung matrix metalloproteinase-9 correlates with cigarette smoking and obstruction of airflow. J Kor Med Sci 18: 821–827Google Scholar
  13. 13.
    Lim S, Roche N, Oliver BG, Mattos W, Barnes PJ, Chung KF (2000) Balance of matrix metalloprotease-9 and tissue inhibitor of metalloprotease-1 from alveolar macrophages in cigarette smokers. Regulation by interleukin-10. Am J Respir Crit Care Med 162: 1355–1360PubMedGoogle Scholar
  14. 14.
    Russell RE, Culpitt SV, DeMatos C, Donnelly L, Smith M, Wiggins J, Barnes PJ (2002) Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 26: 602–609PubMedGoogle Scholar
  15. 15.
    Russell RE, Thorley A, Culpitt SV, Dodd S, Donnelly LE, Demattos C, Fitzgerald M, Barnes PJ (2002) Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases. Am J Physiol Long Cell Mol Physiol 283: L867–L873Google Scholar
  16. 16.
    Cataldo D, Munaut C, Noel A, Frankenne F, Bartsch P, Foidart JM, Louis R (2000) MMP-2-and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease. Int Arch Allergy Immunol 123: 259–267PubMedCrossRefGoogle Scholar
  17. 17.
    Boschetto P, Quintavalle S, Zeni E, Leprotti S, Potena A, Ballerin L, Papi A, Palladini G, Luisetti M, Annovazzi L et al (2006) Association between markers of emphysema and more severe chronic obstructive pulmonary disease. Thorax 61: 1037–1042PubMedCrossRefGoogle Scholar
  18. 18.
    Atkinson JJ, Senior RM (2003) Matrix metalloproteinase-9 in lung remodeling. Am J Respir Cell Mol Biol 28: 12–24PubMedCrossRefGoogle Scholar
  19. 19.
    Shapiro SD, Kobayashi DK, Ley TJ (1993). Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. J Biol Chem 268: 23824–23829PubMedGoogle Scholar
  20. 20.
    Gronski TJ, Martin RL, Kobayashi DK, Walsh BC, Holman M, Huber M, Van Wart HE, Shapiro SD (1997) Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase. J Biol Chem 272: 12189–12194PubMedCrossRefGoogle Scholar
  21. 21.
    Starcher BC (1986) Elastin and the lung. Thorax 41: 577–585PubMedCrossRefGoogle Scholar
  22. 22.
    Shapiro SD (2000) Evolving concepts in the pathogenesis of chronic obstructive pulmonary disease. Clinical Chest Medical 21: 621–632CrossRefGoogle Scholar
  23. 23.
    Stone PJ, Gottlieb DJ, O’Connor GT, Ciccolella DE, Breuer R, Bryan-Rhadfi J, Shaw HA, Franzblau C, Snider GL (1995) Elastin and collagen degradation products in urine of smokers with and without chronic obstructive pulmonary disease. Am J Respir Crit Care Med 151: 952–959PubMedGoogle Scholar
  24. 24.
    Gottlieb DJ, Stone PJ, Sparrow D, Gale ME, Weiss ST, Snider GL, O’Connor GT (1996) Urinary desmosine excretion in smokers with and without rapid decline of lung function: the Normative Aging Study. Am J Respir Crit Care Med 154: 1290–1295PubMedGoogle Scholar
  25. 25.
    Molet S, Belleguic C, Léna H, Germain N, Bertrand CP, Shapiro SD, Planquois JM, Delaval P, Lagente V (2004) Increase in macrophage elastase (MMP-12) in lungs from patients with chronic obstructive pulmonary disease. Inflamm Res 54: 31–36CrossRefGoogle Scholar
  26. 26.
    Demedts IK, Morel-Montero A, Lebecque S, Pacheco Y, Cataldo D, Joos GF (2006) Elevated MMP-12 protein levels in induced sputum from patients with COPD. Thorax 61: 196–201PubMedCrossRefGoogle Scholar
  27. 27.
    Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD (1997). Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277: 2002–2004PubMedCrossRefGoogle Scholar
  28. 28.
    Senior RM, Griffin GL, Mecham RP (1980) Chemotactic activity of elastin-derived peptides. J Clin Invest 66: 859–862PubMedCrossRefGoogle Scholar
  29. 29.
    Houghton AM, Quintero PA, Perkins DL, Kobayashi DK, Kelley DG, Marconcini LA, Mecham RP, Senior RM, Shapiro SD (2006) Elastin fragments drive disease progression in a murine model of emphysema. J Clin Invest 116: 753–759PubMedCrossRefGoogle Scholar
  30. 30.
    Valença SS, Da Hora K, Castro P, Gonçalves de Moraes V, Carvalho L, Moraes Sobrino Porto LC (2004) Emphysema and metalloelastase expression in mouse lung induced by cigarette smoke. Tox Pathol 32: 351–356CrossRefGoogle Scholar
  31. 31.
    Churg A, Zay K, Shay S, Xie C, Shapiro SD, Hendricks R, Wright JL (2002) Acute cigarette smoke-induced connective tissue breakdown requires both neutrophils and macrophage metalloelastase in mice. Am J Respir Cell Mol Biol 27: 368–374PubMedGoogle Scholar
  32. 32.
    Leclerc O, Lagente V, Planquois JM, Berthelier C, Artola M, Eichholtz T, Bertrand CP, Schmidlin F (2006) Involvement of MMP-12 and phosphodiesterase type 4 in cigarette smoke-induced inflammation in mice. Eur Respir J 27: 1102–1109PubMedCrossRefGoogle Scholar
  33. 33.
    Manoury B, Nenan S, Guenon I, Boichot E, Planquois JM, Bertrand CP, Lagente V (2006) Macrophage metalloelastase (MMP-12) deficiency does not alter bleomycininduced pulmonary fibrosis in mice. J Inflamm (Lond) 22: 2CrossRefGoogle Scholar
  34. 34.
    Matute-Bello G, Wurfel MM, Lee JS, Park DR, Frevert CW, Madtes DK, Shapiro SD, Martin TR (2007) Essential role of MMP-12 in Fas-induced lung fibrosis. Am J Respir Cell Mol Biol 37: 210–221PubMedCrossRefGoogle Scholar
  35. 35.
    Nenan S, Planquois JM, Berna P, De Mendez I, Hitier S, Shapiro SD, Boichot E, Lagente V, Bertrand CP (2005) Analysis of the inflammatory response induced by rhMMP-12 catalytic domain instilled in mouse airways. Int Immunopharmacol 5: 511–524PubMedCrossRefGoogle Scholar
  36. 36.
    Nenan S, Lagente V, Planquois JM, Hitier S, Berna P, Bertrand CP, Boichot E (2007) Metalloelastase (MMP-12) induced inflammatory response in mice airways: effects of dexamethasone, rolipram and marimastat. Eur J Pharmacol 559: 75–81PubMedCrossRefGoogle Scholar
  37. 37.
    Selman M, Cisneros-Lira J, Gaxiola M, Ramirez R, Kudlacz EM, Mitchell PG, Pardo A (2003) Matrix metalloproteinases inhibition attenuates tobacco smoke-induced emphysema in Guinea pigs. Chest 123: 1633–1641PubMedCrossRefGoogle Scholar
  38. 38.
    Martin RL, Shapiro SD, Tong SE, Van Wart HE (2001) Macrophage metalloelastase inhibitors. Prog Respir Res 31: 177–180CrossRefGoogle Scholar
  39. 39.
    Churg A, Wang R, Wang X, Onnervik PO, Thim K, Wright JL (2007) Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodeling in guinea pigs. Thorax 62: 706–713PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2008

Authors and Affiliations

  • Catherine le Quément
    • 1
  • Vincent Lagente
    • 1
  • Isabelle Guénon
    • 1
  • Valeria Muzio
    • 2
  • Jean-Yves Gillon
    • 3
  • Elisabeth Boichot
    • 1
  1. 1.INSERM U620, Faculté de PharmacieUniversité de Rennes 1RennesFrance
  2. 2.LCG-RBMIstituto di Ricerche Biomediche “Antoine Marxer”Colleretto GiacosaItaly
  3. 3.Merck-Serono International S.A.Geneva 20Switzerland

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