The Pro-Inflammatory but not Protective Effects of Protease-Activated-Receptor-2 In the Airways are Abolished in Beta-Arrestin-2 Mice in OVA, Cockroach Frass and Alternaria-Induced Models of Allergic Asthma
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Medientyp:
E-Book
Titel:
The Pro-Inflammatory but not Protective Effects of Protease-Activated-Receptor-2 In the Airways are Abolished in Beta-Arrestin-2 Mice in OVA, Cockroach Frass and Alternaria-Induced Models of Allergic Asthma
Erschienen:
[Erscheinungsort nicht ermittelbar]: eScholarship, University of California, 2012
Sprache:
Englisch
Entstehung:
Hochschulschrift:
Dissertation, eScholarship, University of California, 2012
Anmerkungen:
Beschreibung:
ABSTRACT OF THE DISSERTATIONThe Pro-Inflammatory but not Protective Effects of Protease-Activated-Receptor-2 In the Airways are Abolished in Beta-Arrestin-2 Mice in OVA, Cockroach Frass and Alternaria-Induced Models of Allergic AsthmabyHeddie Lynn NicholsDoctor of Philosophy, Graduate Program in Biomedical SciencesUniversity of California, Riverside, December 2012Dr. Kathryn A. DeFeaProteinase Activated Receptor-2 (PAR 2 ), a G Protein Coupled Receptor (GPCR) activated by serine-like proteases, is reported to have both protective and pro-inflammatory effects in the airway. Given these dual and apparently opposing actions, both inhibitors and activators of PAR 2 have been proposed as therapeutics for asthma. PAR 2 can signal through two independent pathways: a G-protein-dependent and a beta--arrestin-2-dependent/G-protein-independent one. The beta-arrestin-dependent pathway promotes leukocyte migration, while bronchiolar smooth muscle relaxation requires G-protein signaling intermediates. These studies address the hypothesis that inflammatory responses to PAR 2 activation are mediated by beta-arrestins, while prostaglandin production and smooth muscle relaxation are not. Our initial studies focused on a mouse ovalbumin model for PAR 2 -modulated airway inflammation to focus specifically on PAR 2 effects. During the course of our studies, two models of PAR 2 dependent airway inflammation were introduced. They are: Alternaria alternata , a fungus that commonly grows in homes and on plant; and Cockroach Frass from Blatella germanica a common household pest. These models induce a more robust inflammatory response and are more physiologically relevant as they used common household allergens. As determined by flow cytometry, cytospin and immunohistochemistry, PAR 2 -induced overall lung inflammation, mucus production, airway responsiveness and recruitment of eosinophils and CD4+-lymphocytes to the Broncho Alveolar Lavage Fluid (BALF) were abolished in beta-arrestin-2-/-, compared with wild type mice. These results were exacerbated in our AltA and BG models. In contrast, PAR 2 promoted equivalent bronchial epithelium-dependent tracheal smooth muscle relaxation and production of PGE2 in both wild type and beta-arrestin-2-/- mice. Our data suggest that the PAR 2 -enhanced inflammatory process is beta-arrestin-2-dependent, while the `protective' anti-constrictor effect of bronchial epithelial PAR 2 is beta-arrestin-independent.