Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults

Mukhopadhyay, Somnath, Sypek, Joseph, Tavendale, Roger, Gartner, Ulrike, Winter, John, Li, Wei, Page, Karen, Fleming, Margaret, Brady, Jeff, O'Toole, Margot, Macgregor, Donald F., Goldman, Samuel, Tam, Steve, Abraham, William, Williams, Cara, Miller, Douglas K. and Palmer, Colin N.A. (2010) Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults. Journal of Allergy and Clinical Immunology, 126 (1). pp. 70-76. ISSN 0091-6749

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Abstract

Background
Matrix metalloproteinase (MMP)-12–mediated pathologic degradation of the extracellular matrix and the subsequent repair cycles influence the airway changes in patients with asthma and chronic obstructive pulmonary disease (COPD). The common serine variant at codon 357 of the MMP12 gene (rs652438) is associated with clinical manifestations consistent with more aggressive matrix degradation in other tissues.

Objective
We sought to explore the hypothesis that MMP12 represents a novel therapeutic target in asthma.

Methods
The role of the rs652438 variant on clinical phenotype was explored in young asthmatic patients and patients with COPD. Candidate MMP-12 inhibitors were identified on the basis of potency and selectivity against a panel of other MMPs. The role of MMP-12–specific inhibition was tested in vitro, as well as in animal models of allergic airway inflammation.

Results
The odds ratio for having greater asthma severity was 2.00 (95% CI, 1.24-3.24; P = .004) when comparing asthmatic patients with at least 1 copy of the serine variant with those with none. The carrier frequency for the variant increased in line with asthma treatment step (P = .000). The presence of the variant nearly doubled the odds in favor of asthmatic exacerbations (odds ratio, 1.90; 95% CI, 1.19-3.04; P = .008) over the previous 6 months. The serine variant was also associated with increased disease severity in patients with COPD (P = .016). Prior administration of an MMP-12–specific inhibitor attenuated the early airway response and completely blocked the late airway response with subsequent Ascaris suum challenge in sheep.

Conclusion
Studies on human participants with asthma and COPD show that the risk MMP12 gene variant is associated with disease severity. In allergen-sensitized sheep pharmacologic inhibition of MMP12 downregulates both early and late airway responses in response to allergic stimuli.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical Medicine
Subjects: Q Science > QR Microbiology > QR0180 Immunology
Depositing User: Grecia GarciaGarcia
Date Deposited: 23 Aug 2011 12:10
Last Modified: 30 Nov 2012 16:55
URI: http://sro.sussex.ac.uk/id/eprint/7313
Google Scholar:5 Citations
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