Journal of Clinical & Experimental Pharmacology

Antagonism of protease activated receptor-2 leads to amelioration of airway reactivity and inflammation via dual oxidase-2 inhibition in a mouse model of allergic asthma

World Congress on Pharmacology

July 20-22, 2015 Brisbane, Australia

Nadeem Ahmed1, Vliagoftis H2 and Tyagi M3

Posters-Accepted Abstracts: Clin Exp Pharmacol

Abstract:

Airway Epithelial Cells (AECs) are involved in allergic airway responses through modulation of a variety of receptors, which sense danger signals from various inhaled aeroallergens/pathogens. Proteinase-Activated Receptor 2 (PAR-2) is one such receptor expressed on innate/adaptive immune cells and is activated by cockroach allergens which have intrinsic serine proteinase activity. Recently, different signaling pathways have been shown to be involved in airway inflammation in response to toll-like receptor activation on innate immune cells. However, the contribution of DUOX-2 signaling in the modulation of airway reactivity, and inflammation after PAR-2 activation/antagonism on AECs has not explored earlier. Therefore, this study specifically focused on AECs isolated from murine trachea to delineate PAR-2 mediated signaling. For this purpose, mice were sensitized intraperitoneally with intact Cockroach allergen Extract (CE) followed by intranasal (i.n.) challenge with CE. The mice were then assessed for airway reactivity, inflammation, and DUOX-2 related oxidative stress (reactive oxygen species, inducible nitric oxide synthase, nitrite, nitrotyrosine and protein carbonyls) and apoptosis (Bax, Bcl-2, caspase-3) in AECs of allergic mice. Challenge with CE led to upregulation of DUOX-2 in AECs with concomitant increases in airway reactivity/ inflammation, and parameters of oxidative stress/apoptosis. Intransal administration of ENMD-1068, a small molecule antagonist of PAR-2 before CE challenge led to improvement of allergic airway reactivity/inflammation through inhibition of DUOX-2 mediated signaling. The data from this study suggest that PAR-2 blockade through inhalation could be utilized as a therapeutic strategy to ameliorate airway reactivity and inflammation in allergic asthma.