title: Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Royal Alexandra Children's Hospital, Brighton and Sussex Medical School, Brighton, United Kingdom. s.mukhopadhyay@bsms.ac.uk
authors.forename: Somnath
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Joseph
authors.initials: J
authors.lastname: Sypek
authors.forename: Roger
authors.initials: R
authors.lastname: Tavendale
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gartner
authors.forename: John
authors.initials: J
authors.lastname: Winter
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Karen
authors.initials: K
authors.lastname: Page
authors.forename: Margaret
authors.initials: M
authors.lastname: Fleming
authors.forename: Jeff
authors.initials: J
authors.lastname: Brady
authors.forename: Margot
authors.initials: M
authors.lastname: O'Toole
authors.forename: Donald F
authors.initials: DF
authors.lastname: Macgregor
authors.forename: Samuel
authors.initials: S
authors.lastname: Goldman
authors.forename: Steve
authors.initials: S
authors.lastname: Tam
authors.forename: William
authors.initials: W
authors.lastname: Abraham
authors.forename: Cara
authors.initials: C
authors.lastname: Williams
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Miller
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D020641:Polymorphism, Single Nucleotide; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012756:Sheep
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D053508:Matrix Metalloproteinase 12