title: P2Y12 antagonist attenuates eosinophilic inflammation and airway hyperresponsiveness in a mouse model of asthma.
abstract: Leukotriene E4 (LTE4) that plays a key role in airway inflammation is expressed on platelets and eosinophils. We investigated whether blocking of the P2Y12 receptor can suppress eosinophilic inflammation in a mouse model of asthma because platelets and eosinophils share this receptor to be activated. BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA), followed by OVA nebulization. On each challenge day, clopidogrel, a P2Y12 antagonist was administered 30 min. before each challenge. Forty-eight hours after the last OVA challenge, mice were assessed for airway hyperresponsiveness (AHR), cell composition and cytokine levels, including chemokine ligand 5 (CCL5), in bronchoalveolar lavage (BAL) fluid. EOL cells were treated with LTE4, with or without clopidogrel treatment, and intracellular and extracellular eosinophil cationic protein (ECP) expressions were measured to find the inhibiting function of P2Y12 antagonist on eosinophilic activation. The levels of P2Y12 expression were increased markedly in the lung homogenates of OVA-sensitized and -challenged mice after platelet depletion. Administration of clopidogrel decreased AHR and the number of airway inflammatory cells, including eosinophils, in BAL fluid following OVA challenge. These results were associated with decreased levels of Th2 cytokines and CCL5. Histological examination showed that inflammatory cells as well as mucus-containing goblet cells were reduced in clopidogrel-administered mice compared to vehicle-treated mice. Clopidogrel inhibited extracellular ECP secretion after LTE4 stimulation in EOL-1 cells. Clopidogrel could prevent development of AHR and airway inflammation in a mouse model of asthma. P2Y12 can be a novel therapeutic target to the suppression of eosinophils in asthma.
authors.affiliation: Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Dong-Hyeon
authors.initials: DH
authors.lastname: Suh
authors.affiliation: Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Hoang Kim Tu
authors.initials: HK
authors.lastname: Trinh
authors.affiliation: Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Jing-Nan
authors.initials: JN
authors.lastname: Liu
authors.affiliation: Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Le Duy
authors.initials: le D
authors.lastname: Pham
authors.affiliation: Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Sang Myun
authors.initials: SM
authors.lastname: Park
authors.affiliation: Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Hae-Sim
authors.initials: HS
authors.lastname: Park
authors.affiliation: Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Yoo Seob
authors.initials: YS
authors.lastname: Shin
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism / Q000473:pathology*; D016535:Bronchial Hyperreactivity / Q000378:metabolism / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000378:metabolism / Q000473:pathology*; D005260:Female; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000494:pharmacology; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*
chemical_list: D016207:Cytokines; C548577:P2ry12 protein, mouse; D058925:Receptors, Purinergic P2Y12; D010047:Ovalbumin
keywords: P2Y12 receptor; asthma; clopidogrel; eosinophil; leukotriene E4