Abstract
Background Proteinase-activated receptor 2 (PAR(2)) is a G protein-coupled receptor activated by trypsin-like serine proteinases. PAR(2) activation has been associated with inflammation including allergic airway inflammation. We have also shown that PAR(2) activation in the airways leads to allergic sensitization. The exact contribution of PAR(2) in the development of eosinophilic inflammation and airway hyperresponsiveness (AHR) in sensitized individuals is not clear.
Objective To investigate whether functional inhibition of PAR(2) 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 PAR(2) in the development of AHR and airway inflammation, we administered blocking anti-PAR(2) antibodies, or a cell permeable peptide inhibitor of PAR(2) signalling, pepducin, i. n. before allergen challenges and then assessed AHR and airway inflammation.
Results Administration of anti-PAR(2) antibodies significantly inhibited OVA-and CEinduced AHR and airway inflammation. In particular, two anti-PAR(2) 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 and Clinical Relevance Functional blockade of PAR(2) in the airways during allergen challenge improves allergen-induced AHR and inflammation in mice. Therefore, topical PAR(2) blockade in the airways, through anti-PAR(2) antibodies or molecules that interrupt PAR(2) signalling, has the potential to be used as a therapeutic option in allergic asthma.