title: Proteinase activated receptor-2-mediated dual oxidase-2 up-regulation is involved in enhanced airway reactivity and inflammation in a mouse model of allergic asthma.
abstract: Airway epithelial cells (AECs) express a variety of receptors, which sense danger signals from various aeroallergens/pathogens being inhaled constantly. Proteinase-activated receptor 2 (PAR-2) is one such receptor and is activated by cockroach allergens, which have intrinsic serine proteinase activity. Recently, dual oxidases (DUOX), especially DUOX-2, have been shown to be involved in airway inflammation in response to Toll-like receptor activation. However, the association between PAR-2 and DUOX-2 has not been explored in airways of allergic mice. Therefore, this study investigated the contribution of DUOX-2/reactive oxygen species (ROS) signalling in airway reactivity and inflammation after PAR-2 activation. Mice were sensitized intraperitoneally with intact cockroach allergen extract (CE) in the presence of aluminium hydroxide followed by intranasal challenge with CE. Mice were then assessed for airway reactivity, inflammation, oxidative stress (DUOX-2, ROS, inducible nitric oxide synthase, nitrite, nitrotyrosine and protein carbonyls) and apoptosis (Bax, Bcl-2, caspase-3). Challenge with CE led to up-regulation of DUOX-2 and ROS in AECs with concomitant increases in airway reactivity/inflammation and parameters of oxidative stress, and apoptosis. All of these changes were significantly inhibited by intranasal administration of ENMD-1068, a small molecule antagonist of PAR-2 in allergic mice. Administration of diphenyliodonium to allergic mice also led to improvement of allergic airway responses via inhibition of the DUOX-2/ROS pathway; however, these effects were less pronounced than PAR-2 antagonism. The current study suggests that PAR-2 activation leads to up-regulation of the DUOX-2/ROS pathway in AECs, which is involved in regulation of airway reactivity and inflammation via oxidative stress and apoptosis.
authors: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Ahmed
authors: A
authors: Nadeem
authors: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Naif O
authors: NO
authors: Alharbi
authors: Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors: Harissios
authors: H
authors: Vliagoftis
authors: Pulmonary Medicine and Critical Care, University of Maryland School of Medicine, Baltimore, MD, USA.
authors: Manoj
authors: M
authors: Tyagi
authors: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Sheikh F
authors: SF
authors: Ahmad
authors: Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors: Mohamed M
authors: MM
authors: Sayed-Ahmed
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D000890:Anti-Infective Agents / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D001713:Biphenyl Compounds / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D003058:Cockroaches; D004195:Disease Models, Animal; D000074623:Dual Oxidases; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D008807:Mice, Inbred BALB C; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D009861:Onium Compounds / Q000276:immunology / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D010879:Piperazines / Q000276:immunology / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D012137:Respiratory System / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: C518710:1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine; D000485:Allergens; D000890:Anti-Infective Agents; D001713:Biphenyl Compounds; D009861:Onium Compounds; D010879:Piperazines; D017382:Reactive Oxygen Species; D044464:Receptor, PAR-2; C031291:diphenyliodonium; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C519130:Duox1 protein, mouse
keywords: airway epithelium; allergic asthma; cockroach extract allergens; dual oxidase-2; proteinase-activated receptor-2; reactive oxygen species