Matrix Metalloproteinases and Their Inhibitors in Chronic Obstructive Pulmonary Disease

  • Zdenka Navratilova
  • Vitezslav Kolek
  • Martin PetrekEmail author


Chronic obstructive pulmonary disease (COPD) is characterised by irreversible airflow limitation associated with chronic inflammation. Matrix metalloproteinases (MMPs) are proteolytic enzymes that contribute to the inflammatory response in COPD and degrade extracellular matrix components. Their enzymatic activity is inhibited by a four-member family of tissue inhibitors of metalloproteinases (TIMPs). In COPD, the MMP/TIMP network, mainly MMP-9, has been repeatedly observed to be dysregulated at both the local (lung) and systemic levels. Here, we review the findings reported in numerous cross-sectional studies with our primary focus on longitudinal observations in human COPD studies. The data from longitudinal prospective studies on the MMP/TIMP network may lead to the introduction of novel prognostic biomarkers into clinical management of COPD. We address the relationship between the systemic and local lung MMP/TIMP network in COPD patients and briefly describe the involvement of microRNAs. Finally, the role of the MMP/TIMP network in COPD treatment is discussed.


Chronic obstructive pulmonary disease Matrix metalloproteinases Tissue inhibitors of metalloproteinases MicroRNAs Local and systemic response Biomarker 



This work was supported by the project CZ.1.07/2.3.00/30.0004 and IGA PU LF 2015 020.


  1. Aaron SD, Vandemheen KL, Ramsay T et al (2010) Multi analyte profiling and variability of inflammatory markers in blood and induced sputum in patients with stable COPD. Respir Res 11:41PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ali S, Banerjee S, Logna F et al (2012) Inactivation of Ink4a/Arf leads to deregulated expression of miRNAs in K-Ras transgenic mouse model of pancreatic cancer. J Cell Physiol 227:3373–3380PubMedPubMedCentralCrossRefGoogle Scholar
  3. Asano K, Shikama Y, Shibuya Y et al (2008) Suppressive activity of tiotropium bromide on matrix metalloproteinase production from lung fibroblasts in vitro. Int J Chron Obstruct Pulmon Dis 3:781–789PubMedPubMedCentralGoogle Scholar
  4. Bafadhel M, McKenna S, Terry S et al (2011) Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med 184:662–671PubMedCrossRefGoogle Scholar
  5. Baines KJ, Simpson JL, Gibson PG (2011) Innate immune responses are increased in chronic obstructive pulmonary disease. PLoS ONE 6:e18426PubMedPubMedCentralCrossRefGoogle Scholar
  6. Barnes NC, Saetta M, Rabe KF (2014) Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast. BMC Pulm Med 14:9PubMedPubMedCentralCrossRefGoogle Scholar
  7. Beasley V, Joshi PV, Singanayagam A et al (2012) Lung microbiology and exacerbations in COPD. Int J Chron Obstr Pulmon Dis 7:555–569Google Scholar
  8. Bolton CE, Stone MD, Edwards PH et al (2009) Circulating matrix metalloproteinase-9 and osteoporosis in patients with chronic obstructive pulmonary disease. Chron Respir Dis 6:81–87PubMedCrossRefGoogle Scholar
  9. Bonnema DD, Webb CS, Pennington WR et al (2007) Effects of age on plasma matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs). J Card Fail 13:530–540PubMedPubMedCentralCrossRefGoogle Scholar
  10. Boosani CS, Agrawal DK (2013) PTEN modulators: a patent review. Expert Opin Ther Pat 23:569–580PubMedPubMedCentralCrossRefGoogle Scholar
  11. Brajer B, Batura-Gabryel H, Nowicka A et al (2008) Concentration of matrix metalloproteinase-9 in serum of patients with chronic obstructive pulmonary disease and a degree of airway obstruction and disease progression. J Physiol Pharmacol 59(Suppl 6):145–152PubMedGoogle Scholar
  12. Brusselle GG, Joos GF, Bracke KR (2011) New insights into the immunology of chronic obstructive pulmonary disease Lancet 378:1015–1026PubMedGoogle Scholar
  13. Burgel PR, Bergeron A, de Blic J et al (2013) Small airways diseases, excluding asthma and COPD: an overview. Eur Respir Rev 22:131–147PubMedCrossRefGoogle Scholar
  14. Cataldo D, Munaut C, Noel A et al (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
  15. Cataldo D, Munaut C, Noel A et al (2001) Matrix metalloproteinases and TIMP-1 production by peripheral blood granulocytes from COPD patients and asthmatics. Allergy 56:145–151PubMedCrossRefGoogle Scholar
  16. Chaudhuri R, McSharry C, Brady J et al (2012) Sputum matrix metalloproteinase-12 in patients with chronic obstructive pulmonary disease and asthma: relationship to disease severity. J Allergy Clin Immunol 129(655–663):e658Google Scholar
  17. Chaudhuri R, McSharry C, Spears M et al (2013) Sputum matrix metalloproteinase-9 is associated with the degree of emphysema on computed tomography in COPD. Translational Respir Med 1:11CrossRefGoogle Scholar
  18. Chelladurai P, Seeger W, Pullamsetti SS (2012) Matrix metalloproteinases and their inhibitors in pulmonary hypertension. Eur Respir J 40:766–782PubMedCrossRefGoogle Scholar
  19. Churg A, Wang R, Wang X et al (2007) Effect of an MMP-9/MMP-12 inhibitor on smoke-induced emphysema and airway remodelling in guinea pigs. Thorax 62:706–713PubMedPubMedCentralCrossRefGoogle Scholar
  20. Churg A, Zhou S, Wright JL (2012) Series “matrix metalloproteinases in lung health and disease”: matrix metalloproteinases in COPD. Eur Respir J 39:197–209PubMedCrossRefGoogle Scholar
  21. Culpitt SV, Maziak W, Loukidis S et al (1999) Effect of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 160:1635–1639PubMedCrossRefGoogle Scholar
  22. Culpitt SV, Rogers DF, Traves SL et al (2005) Sputum matrix metalloproteases: comparison between chronic obstructive pulmonary disease and asthma. Respir Med 99:703–710PubMedCrossRefGoogle Scholar
  23. Dahl R, Titlestad I, Lindqvist A et al (2012) Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trial. Pulm Pharmacol Ther 25:169–177PubMedCrossRefGoogle Scholar
  24. D’Armiento JM, Goldklang MP, Hardigan AA et al (2013) Increased matrix metalloproteinase (MMPs) levels do not predict disease severity or progression in emphysema. PLoS ONE 8:e56352PubMedPubMedCentralCrossRefGoogle Scholar
  25. Davey A, McAuley DF, O’Kane CM (2011) Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair. Eur Respir J 38:959–970PubMedCrossRefGoogle Scholar
  26. Demedts IK, Morel-Montero A, Lebecque S et al (2006) Elevated MMP-12 protein levels in induced sputum from patients with COPD. Thorax 61:196–201PubMedPubMedCentralCrossRefGoogle Scholar
  27. Deshmukh HS, McLachlan A, Atkinson JJ et al (2009) Matrix metalloproteinase-14 mediates a phenotypic shift in the airways to increase mucin production. Am J Respir Crit Care Med 180:834–845PubMedPubMedCentralCrossRefGoogle Scholar
  28. Devenport NA, Reynolds JC, Parkash V et al (2011) Determination of free desmosine and isodesmosine as urinary biomarkers of lung disorder using ultra performance liquid chromatography-ion mobility-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 879:3797–3801PubMedCrossRefGoogle Scholar
  29. Dickens JA, Miller BE, Edwards LD et al (2011) COPD association and repeatability of blood biomarkers in the ECLIPSE cohort. Respir Res 12:146PubMedPubMedCentralCrossRefGoogle Scholar
  30. Ezzie ME, Crawford M, Cho JH et al (2012) Gene expression networks in COPD: microRNA and mRNA regulation. Thorax 67:122–131PubMedCrossRefGoogle Scholar
  31. Fata JE, Debnath S, Jenkins EC Jr et al (2012) Nongenomic mechanisms of PTEN regulation. Int J Cell Biol 2012:379685PubMedPubMedCentralCrossRefGoogle Scholar
  32. Finlay GA, O’Driscoll LR, Russell KJ et al (1997) Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Respir Crit Care Med 156:240–247PubMedCrossRefGoogle Scholar
  33. Gabriely G, Wurdinger T, Kesari S et al (2008) MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol 28:5369–5380PubMedPubMedCentralCrossRefGoogle Scholar
  34. Ganesan S, Faris AN, Comstock AT et al (2010) Quercetin prevents progression of disease in elastase/LPS-exposed mice by negatively regulating MMP expression. Respir Res 11:131PubMedPubMedCentralCrossRefGoogle Scholar
  35. Gao Z, Ye J (2008) Inhibition of transcriptional activity of c-JUN by SIRT1. Biochem Biophys Res Commun 376:793–796PubMedPubMedCentralCrossRefGoogle Scholar
  36. Gao P, Zhang J, He X et al (2013) Sputum inflammatory cell-based classification of patients with acute exacerbation of chronic obstructive pulmonary disease. PLoS ONE 8:e57678PubMedPubMedCentralCrossRefGoogle Scholar
  37. Garofalo M, Di Leva G, Romano G et al (2009) miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 16:498–509PubMedPubMedCentralCrossRefGoogle Scholar
  38. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) (2015)
  39. Gosselink JV, Hayashi S, Elliott WM et al (2010) Differential expression of tissue repair genes in the pathogenesis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 181:1329–1335PubMedPubMedCentralCrossRefGoogle Scholar
  40. Graff JW, Powers LS, Dickson AM et al (2012) Cigarette smoking decreases global microRNA expression in human alveolar macrophages. PLoS ONE 7:e44066PubMedPubMedCentralCrossRefGoogle Scholar
  41. Grootendorst DC, Gauw SA, Verhoosel RM et al (2007) Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 62:1081–1087PubMedPubMedCentralCrossRefGoogle Scholar
  42. Growcott EJ, Spink KG, Ren X et al (2006) Phosphodiesterase type 4 expression and anti-proliferative effects in human pulmonary artery smooth muscle cells. Respir Res 7:9PubMedPubMedCentralCrossRefGoogle Scholar
  43. Hamada S, Satoh K, Fujibuchi W et al (2012) MiR-126 acts as a tumor suppressor in pancreatic cancer cells via the regulation of ADAM9. Mol Cancer Res 10:3–10PubMedCrossRefGoogle Scholar
  44. Harju T, Kinnula VL, Paakko P et al (2010) Variability in the precursor proteins of collagen I and III in different stages of COPD. Respir Res 11:165PubMedPubMedCentralCrossRefGoogle Scholar
  45. Higashimoto Y, Yamagata Y, Iwata T et al (2005) Increased serum concentrations of tissue inhibitor of metalloproteinase-1 in COPD patients. Eur Respir J 25:885–890PubMedCrossRefGoogle Scholar
  46. Higashimoto Y, Iwata T, Okada MY et al (2009) Serum biomarkers as predictors of lung function decline in chronic obstructive pulmonary disease. Respir Med 103:1231–1238PubMedCrossRefGoogle Scholar
  47. Hoenderdos K, Condliffe A (2013) The neutrophil in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 48:531–539PubMedCrossRefGoogle Scholar
  48. Hurst JR, Donaldson GC, Perera WR et al (2006) Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 174:867–874PubMedCrossRefGoogle Scholar
  49. Ilumets H, Rytilä P, Demedts I et al (2007) Matrix metalloproteinases -8, -9 and -12 in smokers and patients with stage 0 COPD. Int J Chron Obstruct Pulm Dis 2:369–379Google Scholar
  50. Ilumets H, Rytila PH, Sovijarvi AR et al (2008) Transient elevation of neutrophil proteinases in induced sputum during COPD exacerbation. Scand J Clin Lab Invest 68:618–623PubMedCrossRefGoogle Scholar
  51. Ilumets H, Mazur W, Toljamo T et al (2011) Ageing and smoking contribute to plasma surfactant proteins and protease imbalance with correlations to airway obstruction. BMC Pulm Med 11:19PubMedPubMedCentralCrossRefGoogle Scholar
  52. Imai K, Dalal SS, Chen ES et al (2001) Human collagenase (matrix metalloproteinase-1) expression in the lungs of patients with emphysema. Am J Respir Crit Care Med 163:786–791PubMedCrossRefGoogle Scholar
  53. Ishii T, Abboud RT, Wallace AM et al (2014) Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema. Eur Respir J 43:82–91PubMedCrossRefGoogle Scholar
  54. Ivanov P, Anderson P (2013) Post-transcriptional regulatory networks in immunity. Immunol Rev 253:253–272PubMedCrossRefGoogle Scholar
  55. Jenkins CR, Celli B, Anderson JA et al (2012) Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study. Eur Respir J 39:38–45PubMedCrossRefGoogle Scholar
  56. Jones NA, Boswell-Smith V, Lever R et al (2005) The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro. Pulm Pharmacol Ther 18:93–101PubMedCrossRefGoogle Scholar
  57. Kanazawa H (2007) Role of vascular endothelial growth factor in the pathogenesis of chronic obstructive pulmonary disease. Med Sci Monit 13:RA189–RA195PubMedGoogle Scholar
  58. Ko FW, Diba C, Roth M et al (2005) A comparison of airway and serum matrix metalloproteinase-9 activity among normal subjects, asthmatic patients, and patients with asthmatic mucus hypersecretion. Chest 127:1919–1927PubMedCrossRefGoogle Scholar
  59. Kwiatkowska S, Noweta K, Zieba M et al (2012) Enhanced exhalation of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in patients with COPD exacerbation: a prospective study. Respiration 84:231–241PubMedCrossRefGoogle Scholar
  60. Lagente V, Naline E, Guenon I et al (2004) A nitric oxide-releasing salbutamol elicits potent relaxant and anti-inflammatory activities. J Pharmacol Exp Ther 310:367–375PubMedCrossRefGoogle Scholar
  61. Lambers C, Qi Y, Eleni P et al (2014) Extracellular matrix composition is modified by beta(2)-agonists through cAMP in COPD. Biochem Pharmacol 91:400–408PubMedCrossRefGoogle Scholar
  62. Le Quement C, Guenon I, Gillon JY et al (2008) The selective MMP-12 inhibitor, AS111793 reduces airway inflammation in mice exposed to cigarette smoke. Br J Pharmacol 154:1206–1215PubMedPubMedCentralCrossRefGoogle Scholar
  63. Lee EJ, In KH, Kim JH et al (2009) Proteomic analysis in lung tissue of smokers and COPD patients. Chest 135:344–352PubMedCrossRefGoogle Scholar
  64. Leeming DJ, Sand JM, Nielsen MJ et al (2012) Serological investigation of the collagen degradation profile of patients with chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis. Biomark Insights 7:119–126PubMedPubMedCentralCrossRefGoogle Scholar
  65. Leidinger P, Keller A, Borries A et al (2011) Specific peripheral miRNA profiles for distinguishing lung cancer from COPD. Lung Cancer 74:41–47PubMedCrossRefGoogle Scholar
  66. Li X, Gibson G, Kim JS et al (2011) MicroRNA-146a is linked to pain-related pathophysiology of osteoarthritis. Gene 480:34–41PubMedPubMedCentralCrossRefGoogle Scholar
  67. Liu X, Yu J, Jiang L et al (2009) MicroRNA-222 regulates cell invasion by targeting matrix metalloproteinase 1 (MMP1) and manganese superoxide dismutase 2 (SOD2) in tongue squamous cell carcinoma cell lines. Cancer Genomics Proteomics 6:131–139PubMedPubMedCentralGoogle Scholar
  68. Loffek S, Schilling O, Franzke CW (2011) Series “matrix metalloproteinases in lung health and disease”: biological role of matrix metalloproteinases: a critical balance. Eur Respir J 38:191–208PubMedCrossRefGoogle Scholar
  69. Louhelainen N, Stark H, Mazur W et al (2010) Elevation of sputum matrix metalloproteinase-9 persists up to 6 months after smoking cessation: a research study. BMC Pulm Med 10:13PubMedPubMedCentralCrossRefGoogle Scholar
  70. Lowrey GE, Henderson N, Blakey JD et al (2008) MMP-9 protein level does not reflect overall MMP activity in the airways of patients with COPD. Respir Med 102:845–851PubMedCrossRefGoogle Scholar
  71. Loza MJ, Watt R, Baribaud F et al (2012) Systemic inflammatory profile and response to anti-tumor necrosis factor therapy in chronic obstructive pulmonary disease. Respir Res 13:12PubMedPubMedCentralCrossRefGoogle Scholar
  72. Lu Y et al (2011) Anti-microRNA-222 (anti-miR-222) and -181B suppress growth of tamoxifen-resistant xenografts in mouse by targeting TIMP3 protein and modulating mitogenic signal. J Biol Chem 286:42292–42302PubMedPubMedCentralCrossRefGoogle Scholar
  73. Ma S, Lin YY, Turino GM (2007) Measurements of desmosine and isodesmosine by mass spectrometry in COPD. Chest 131:1363–1371PubMedCrossRefGoogle Scholar
  74. Ma X, Becker Buscaglia LE, Barker JR et al (2011) MicroRNAs in NF-kappaB signaling. J Mol Cell Biol 3:159–166PubMedPubMedCentralCrossRefGoogle Scholar
  75. Maclay JD et al (2012) Systemic elastin degradation in chronic obstructive pulmonary disease. Thorax 67:606–612PubMedCrossRefGoogle Scholar
  76. Meng F, Henson R, Wehbe-Janek H et al (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133:647–658PubMedPubMedCentralCrossRefGoogle Scholar
  77. Mercer PF, Shute JK, Bhowmik A et al (2005) MMP-9, TIMP-1 and inflammatory cells in sputum from COPD patients during exacerbation. Respir Res 6:151PubMedPubMedCentralCrossRefGoogle Scholar
  78. Milara J, Lluch J, Almudever P et al (2014) Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 134:314–322PubMedCrossRefGoogle Scholar
  79. Millares L, Marin A, Garcia-Aymerich J et al (2012) Specific IgA and metalloproteinase activity in bronchial secretions from stable chronic obstructive pulmonary disease patients colonized by Haemophilus influenzae. Respir Res 13:113PubMedPubMedCentralCrossRefGoogle Scholar
  80. Molina-Pinelo S, Pastor MD, Suarez R et al (2014) MicroRNA clusters: dysregulation in lung adenocarcinoma and COPD. Eur Respir J 43:1740–1749PubMedCrossRefGoogle Scholar
  81. Mu W, Zhang W (2012) Bioinformatic resources of microRNA sequences, gene targets, and genetic variation. Front Genet 3:31PubMedPubMedCentralCrossRefGoogle Scholar
  82. Muller KC, Welker L, Paasch K et al (2006) Lung fibroblasts from patients with emphysema show markers of senescence in vitro. Respir Res 7:32PubMedPubMedCentralCrossRefGoogle Scholar
  83. Murakami Y, Toyoda H, Tanaka M et al (2011) The progression of liver fibrosis is related with overexpression of the miR-199 and 200 families. PLoS ONE 6:e16081PubMedPubMedCentralCrossRefGoogle Scholar
  84. Nakamaru Y, Vuppusetty C, Wada H et al (2009) A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9. FASEB J 23:2810–2819PubMedCrossRefGoogle Scholar
  85. Navratilova Z, Zatloukal J, Kriegova E et al (2012) Simultaneous up-regulation of matrix metalloproteinases 1, 2, 3, 7, 8, 9 and tissue inhibitors of metalloproteinases 1, 4 in serum of patients with chronic obstructive pulmonary disease. Respirology 17:1006–1012PubMedCrossRefGoogle Scholar
  86. Noguera A, Gomez C, Faner R et al (2012) An investigation of the resolution of inflammation (catabasis) in COPD. Respir Res 13:101PubMedPubMedCentralCrossRefGoogle Scholar
  87. Olafsdottir IS, Janson C, Lind L et al (2010) Serum levels of matrix metalloproteinase-9, tissue inhibitors of metalloproteinase-1 and their ratio are associated with impaired lung function in the elderly: a population-based study. Respirology 15:530–535PubMedCrossRefGoogle Scholar
  88. Omachi TA, Eisner MD, Rames A et al (2011) Matrix metalloproteinase-9 predicts pulmonary status declines in alpha1-antitrypsin deficiency. Respir Res 12:35PubMedPubMedCentralCrossRefGoogle Scholar
  89. Paone G, Conti V, Vestri A et al (2011) Analysis of sputum markers in the evaluation of lung inflammation and functional impairment in symptomatic smokers and COPD patients. Dis Markers 31:91–100PubMedPubMedCentralCrossRefGoogle Scholar
  90. Park HY, Churg A, Wright JL et al (2013) Club cell protein 16 and disease progression in chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med 188:1413–1419PubMedPubMedCentralCrossRefGoogle Scholar
  91. Perng DW, Tao CW, Su KC et al (2009) Anti-inflammatory effects of salmeterol/fluticasone, tiotropium/fluticasone or tiotropium in COPD. Eur Respir J 33:778–784PubMedCrossRefGoogle Scholar
  92. Perng DW, Su KC, Chou KT et al (2012) Long-acting beta2 agonists and corticosteroids restore the reduction of histone deacetylase activity and inhibit H2O2-induced mediator release from alveolar macrophages. Pulm Pharmacol Ther 25:312–318PubMedCrossRefGoogle Scholar
  93. Philibert RA, Sears RA, Powers LS et al (2012) Coordinated DNA methylation and gene expression changes in smoker alveolar macrophages: specific effects on VEGF receptor 1 expression. J Leukoc Biol 92:621–631PubMedPubMedCentralCrossRefGoogle Scholar
  94. Pinkerton M, Chinchilli V, Banta E et al (2013) Differential expression of microRNAs in exhaled breath condensates of patients with asthma, patients with chronic obstructive pulmonary disease, and healthy adults. J Allergy Clin Immunol 132:217–219PubMedCrossRefGoogle Scholar
  95. Pinto-Plata V, Toso J, Lee K et al (2007) Profiling serum biomarkers in patients with COPD: associations with clinical parameters. Thorax 62:595–601PubMedPubMedCentralCrossRefGoogle Scholar
  96. Pinto-Plata V, Casanova C, Müllerova H et al (2012) Inflammatory and repair serum biomarker pattern. Association to clinical outcomes in COPD. Respir Res 13:71PubMedPubMedCentralCrossRefGoogle Scholar
  97. Ropcke S, Holz O, Lauer G et al (2012) Repeatability of and relationship between potential COPD biomarkers in bronchoalveolar lavage, bronchial biopsies, serum, and induced sputum. PLoS ONE 7:e46207PubMedPubMedCentralCrossRefGoogle Scholar
  98. Russell RE, Culpitt SV, DeMatos C et al (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 Biology 26:602–609CrossRefGoogle Scholar
  99. Schembri F, Sridhar S, Perdomo C et al (2009) MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium. Proc Natl Acad Sci USA 106:2319–2324PubMedPubMedCentralCrossRefGoogle Scholar
  100. Segura-Valdez L, Pardo A, Gaxiola M et al (2000) Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 117:684–694PubMedCrossRefGoogle Scholar
  101. Sethi S, Maloney J, Grove L et al (2006) Airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 173:991–998PubMedPubMedCentralCrossRefGoogle Scholar
  102. Shaker SB, von Wachenfeldt KA, Larsson S et al (2008) Identification of patients with chronic obstructive pulmonary disease (COPD) by measurement of plasma biomarkers. Clin Respir J 2:17–25PubMedCrossRefGoogle Scholar
  103. Shaykhiev R, Otaki F, Bonsu P et al (2011) Cigarette smoking reprograms apical junctional complex molecular architecture in the human airway epithelium in vivo. Cell Mol Life Sci 68:877–892PubMedCrossRefGoogle Scholar
  104. Simpson JL, McDonald VM, Baines KJ et al (2013) Influence of age, past smoking, and disease severity on TLR2, neutrophilic inflammation, and MMP-9 levels in COPD. Mediators Inflamm 2013:462934PubMedPubMedCentralCrossRefGoogle Scholar
  105. Sing T, Jinnin M, Yamane K et al (2012) microRNA-92a expression in the sera and dermal fibroblasts increases in patients with scleroderma. Rheumatology 51:1550–1556PubMedCrossRefGoogle Scholar
  106. Skjot-Arkil H, Clausen RE, Nguyen QH et al (2012) Measurement of MMP-9 and -12 degraded elastin (ELM) provides unique information on lung tissue degradation. BMC Pulm Med 12:34PubMedPubMedCentralCrossRefGoogle Scholar
  107. Snitker S, Xie K, Ryan KA et al (2013) Correlation of circulating MMP-9 with white blood cell count in humans: effect of smoking. PLoS ONE 8:e66277PubMedPubMedCentralCrossRefGoogle Scholar
  108. Stanczyk J, Ospelt C, Karouzakis E et al (2011) Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum 63:373–381PubMedPubMedCentralCrossRefGoogle Scholar
  109. Sturgeon C, Hill R, Hortin GL et al (2010) Taking a new biomarker into routine use—a perspective from the routine clinical biochemistry laboratory. Proteomics Clin Appl 4:892–903PubMedPubMedCentralCrossRefGoogle Scholar
  110. Takahashi C, Sheng Z, Horan TP et al (1998) Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc Natl Acad Sci USA 95:13221–13226PubMedPubMedCentralCrossRefGoogle Scholar
  111. Tashkin DP, Celli B, Senn S et al (2008) A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 359:1543–1554PubMedCrossRefGoogle Scholar
  112. Thomsen M, Ingebrigtsen TS, Marott JL et al (2013) Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA 309:2353–2361PubMedCrossRefGoogle Scholar
  113. van Noord JA, de Munck DR, Bantje TAAM et al (2000) Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. Eur Respir J 15:878–885PubMedCrossRefGoogle Scholar
  114. Van Pottelberge GR, Mestdagh P, Bracke KR et al (2011) MicroRNA expression in induced sputum of smokers and patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 183:898–906PubMedCrossRefGoogle Scholar
  115. Vergoulis T, Vlachos IS, Alexiou P et al (2012) TarBase 6.0: capturing the exponential growth of miRNA targets with experimental support. Nucleic Acids Res 40:D222–D229PubMedPubMedCentralCrossRefGoogle Scholar
  116. Vernooy JH, Lindeman JH, Jacobs JA et al (2004) Increased activity of matrix metalloproteinase-8 and matrix metalloproteinase-9 in induced sputum from patients with COPD. Chest 126:1802–1810PubMedCrossRefGoogle Scholar
  117. Vestbo J, Hurd SS, Rodriguez-Roisin R (2012) The 2011 revision of the global strategy for the diagnosis, management and prevention of COPD (GOLD)—why and what? Clin Respir J 6:208–214PubMedCrossRefGoogle Scholar
  118. Vestbo J, Hurd SS, Agustí AG et al (2013) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 187:347–365PubMedCrossRefGoogle Scholar
  119. Vignola AM, Riccobono L, Mirabella A et al (1998) Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am J Respir Crit Care Med 158:1945–1950PubMedCrossRefGoogle Scholar
  120. Vlahos R, Wark PA, Anderson GP et al (2012) Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD. PLoS ONE 7:e33277PubMedPubMedCentralCrossRefGoogle Scholar
  121. Vucic EA, Chari R, Thu KL et al (2014) DNA methylation is globally disrupted and associated with expression changes in chronic obstructive pulmonary disease small airways. Am J Respir Cell Mol Biol 50:912–922PubMedPubMedCentralCrossRefGoogle Scholar
  122. Wallace AM, Sandford AJ, English JC et al (2008) Matrix metalloproteinase expression by human alveolar macrophages in relation to emphysema. COPD 5:13–23PubMedCrossRefGoogle Scholar
  123. Wang IM, Stepaniants S, Boie Y et al (2008) Gene expression profiling in patients with chronic obstructive pulmonary disease and lung cancer. Am J Respir Crit Care Med 177:402–411PubMedCrossRefGoogle Scholar
  124. Wedzicha JA, Rabe KF, Martinez FJ et al (2013) Efficacy of roflumilast in the COPD frequent exacerbator phenotype. Chest 143:1302–1311PubMedCrossRefGoogle Scholar
  125. Wouters EF, Reynaert NL, Dentener MA et al (2009) Systemic and local inflammation in asthma and chronic obstructive pulmonary disease: is there a connection? Proc Am Thorac Soc 6:638–647PubMedCrossRefGoogle Scholar
  126. Wu Y, Li J, Wu J et al (2012) Discovery of potent and selective matrix metalloprotease 12 inhibitors for the potential treatment of chronic obstructive pulmonary disease (COPD). Bioorg Med Chem Lett 22:138–143PubMedCrossRefGoogle Scholar
  127. Xu N, Zhang L, Meisgen F et al (2012) MicroRNA-125b down-regulates matrix metallopeptidase 13 and inhibits cutaneous squamous cell carcinoma cell proliferation, migration, and invasion. J Biol Chem 287:29899–29908PubMedPubMedCentralCrossRefGoogle Scholar
  128. Yao H, Hwang JW, Sundar IK et al (2013) SIRT1 redresses the imbalance of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9 in the development of mouse emphysema and human COPD. Am J Physiol Lung Cell Mol Physiol 305:L615–L624PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2015

Authors and Affiliations

  • Zdenka Navratilova
    • 1
  • Vitezslav Kolek
    • 2
  • Martin Petrek
    • 1
    Email author
  1. 1.Laboratory of Immunogenomics, Department of Pathological Physiology, Faculty of Medicine and DentistryPalacky UniversityOlomoucCzech Republic
  2. 2.Department of Respiratory Medicine, Faculty of Medicine and DentistryPalacky UniversityOlomoucCzech Republic

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