Sputum Matrix Metalloproteinases (MMP) mRNA and Montelukast

Summary

Matrix metalloproteinases (MMPs) are a group of 24 zinc containing enzymes in man. These enzymes were originally described as cleaving extracellular matrix (ECM) substrates with a predominant role in ECM homeostasis, but it is now clear that they have much wider functionality. An imbalance between MMP activity and that of their inhibitors (tissue inhibitors of metalloproteinases, TIMPs) is considered to play a critical role in the synthesis or degradation of the extracellular matrix of the airway architecture which results in fixed airflow obstruction in both asthma and chronic obstructive pulmonary disease (COPD). Using quantitative real time polymerase chain reaction (RT-PCR) the investigators have identified a difference between the level of steady state mRNA for MMP-9, MMP-14 and MMP-2 in 2 patients with asthma compared to 4 healthy controls using our method. However the investigators require further refinement of the process in order to optimise RNA quality and to evaluate the effect of montelukast across the entire family of MMPs and their inhibitors (TIMPs).

Timeline

Start

2009-07

Primary completion

2011-12

Completion

2011-12

Publications

• Background Cauwe B, Van den Steen PE, Opdenakker G. The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol. 2007 May-Jun;42(3):113-85. doi: 10.1080/10409230701340019.
• Background Suzuki R, Miyazaki Y, Takagi K, Torii K, Taniguchi H. Matrix metalloproteinases in the pathogenesis of asthma and COPD: implications for therapy. Treat Respir Med. 2004;3(1):17-27. doi: 10.2165/00151829-200403010-00003.
• Background Atkinson JJ, Senior RM. Matrix metalloproteinase-9 in lung remodeling. Am J Respir Cell Mol Biol. 2003 Jan;28(1):12-24. doi: 10.1165/rcmb.2002-0166TR.
• Background Kelly EA, Busse WW, Jarjour NN. Increased matrix metalloproteinase-9 in the airway after allergen challenge. Am J Respir Crit Care Med. 2000 Sep;162(3 Pt 1):1157-61. doi: 10.1164/ajrccm.162.3.9908016.
• Background Boulay ME, Prince P, Deschesnes F, Chakir J, Boulet LP. Metalloproteinase-9 in induced sputum correlates with the severity of the late allergen-induced asthmatic response. Respiration. 2004 May-Jun;71(3):216-24. doi: 10.1159/000077418.
• Background Beeh KM, 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 Jun;97(6):634-9. doi: 10.1053/rmed.2003.1493.
• Background Vignola AM, Riccobono L, Mirabella A, Profita M, Chanez P, Bellia V, Mautino G, D'accardi P, Bousquet J, Bonsignore G. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am J Respir Crit Care Med. 1998 Dec;158(6):1945-50. doi: 10.1164/ajrccm.158.6.9803014.
• Background Barnes PJ, Hansel TT. Prospects for new drugs for chronic obstructive pulmonary disease. Lancet. 2004 Sep 11-17;364(9438):985-96. doi: 10.1016/S0140-6736(04)17025-6.
• Background Langlois A, Ferland C, Tremblay GM, Laviolette M. Montelukast regulates eosinophil protease activity through a leukotriene-independent mechanism. J Allergy Clin Immunol. 2006 Jul;118(1):113-9. doi: 10.1016/j.jaci.2006.03.010. Epub 2006 May 19.
• Background Vignola AM, Riccobono L, Profita M, Foresi A, Di Giorgi R, Guerrera D, Gjomarkaj M, Di Blasi P, Paggiaro PL. Effects of low doses of inhaled fluticasone propionate on inflammation and remodelling in persistent-mild asthma. Allergy. 2005 Dec;60(12):1511-7. doi: 10.1111/j.1398-9995.2005.00827.x.
• Background Chuang SS, Hung CH, Hua YM, Tien CH, Yang KD, Jong YJ, Hsu SH, Lin CS. Suppression of plasma matrix metalloproteinase-9 following montelukast treatment in childhood asthma. Pediatr Int. 2007 Dec;49(6):918-22. doi: 10.1111/j.1442-200X.2007.02497.x.
• Background Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone L, Porter S, Brockbank SM, Edwards DR, Parker AE, Clark IM. Expression profiling of metalloproteinases and their inhibitors in cartilage. Arthritis Rheum. 2004 Jan;50(1):131-41. doi: 10.1002/art.11433.
• Background Standardization of spirometry--1987 update. Statement of the American Thoracic Society. Am Rev Respir Dis. 1987 Nov;136(5):1285-98. doi: 10.1164/ajrccm/136.5.1285. No abstract available.
• Background Pizzichini E, Pizzichini MM, Efthimiadis A, Evans S, Morris MM, Squillace D, Gleich GJ, Dolovich J, Hargreave FE. Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care Med. 1996 Aug;154(2 Pt 1):308-17. doi: 10.1164/ajrccm.154.2.8756799.

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Indications