title: Functional inhibition of PAR2 alleviates allergen-induced airway hyperresponsiveness and inflammation.
abstract: BACKGROUND
  Proteinase-activated receptor 2 (PAR2 ) is a G protein-coupled receptor activated by trypsin-like serine proteinases. PAR2 activation has been associated with inflammation including allergic airway inflammation. We have also shown that PAR2 activation in the airways leads to allergic sensitization. The exact contribution of PAR2 in the development of eosinophilic inflammation and airway hyperresponsiveness (AHR) in sensitized individuals is not clear.
  
  
  OBJECTIVE
  To investigate whether functional inhibition of PAR2 during allergen challenge of allergic mice would inhibit allergen-induced AHR and inflammation in mouse models of asthma.
  
  
  METHODS
  Mice were sensitized and challenged with ovalbumin (OVA) or cockroach extract (CE). To investigate the role of PAR2 in the development of AHR and airway inflammation, we administered blocking anti-PAR2 antibodies, or a cell permeable peptide inhibitor of PAR2 signalling, pepducin, i.n. before allergen challenges and then assessed AHR and airway inflammation.
  
  
  RESULTS
  Administration of anti-PAR2 antibodies significantly inhibited OVA- and CE-induced AHR and airway inflammation. In particular, two anti-PAR2 antibodies, the monoclonal SAM-11 and polyclonal B5, inhibited AHR, airway eosinophilia, the increase of cytokines in the lung tissue and antigen-specific T cell proliferation, but had no effect on antigen-specific IgG and IgE levels. Pepducin was also effective in inhibiting AHR and airway inflammation in an OVA model of allergic airway inflammation.
  
  
  CONCLUSIONS
  Functional blockade of PAR2 in the airways during allergen challenge improves allergen-induced AHR and inflammation in mice. Therefore, topical PAR2 blockade in the airways, through anti-PAR2 antibodies or molecules that interrupt PAR2 signalling, has the potential to be used as a therapeutic option in allergic asthma.
authors: Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors: M
authors: M
authors: Asaduzzaman
authors: Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors: A
authors: A
authors: Nadeem
authors: Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors: N
authors: N
authors: Arizmendi
authors: Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors: C
authors: C
authors: Davidson
authors: Division of Biomedical Sciences and Cell, Molecular and Developmental Biology, University of California, Riverside, CA, USA.
authors: H L
authors: HL
authors: Nichols
authors: Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors: M
authors: M
authors: Abel
authors: Department of Physiology, Women and Children Health Research Institute, University of Alberta, Edmonton, AB, Canada.
authors: L I
authors: LI
authors: Ionescu
authors: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
authors: L
authors: L
authors: Puttagunta
authors: Department of Physiology, Women and Children Health Research Institute, University of Alberta, Edmonton, AB, Canada.
authors: B
authors: B
authors: Thebaud
authors: Immunology Research Group, University of Saskatchewan, Saskatoon, SK, Canada.
authors: J
authors: J
authors: Gordon
authors: Division of Biomedical Sciences and Cell, Molecular and Developmental Biology, University of California, Riverside, CA, USA.
authors: K
authors: K
authors: DeFea
authors: Department of Pharmacology and Therapeutics, University of Calgary, Calgary, AB, Canada.
authors: M D
authors: MD
authors: Hollenberg
authors: Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors: H
authors: H
authors: Vliagoftis
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015415:Biomarkers; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D007114:Immunization; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors*; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D016207:Cytokines; D007074:Immunoglobulin G; D044464:Receptor, PAR-2; D007073:Immunoglobulin E; D010047:Ovalbumin
keywords: airway inflammation; asthma; cockroach; mouse; ovalbumin; proteinase-activated receptor 2