title: Chemokines mediate ethanol-induced exacerbations of murine cockroach allergen asthma.
abstract: Asthma imposes considerable patient and economic burdens, with the most severe cases causing the greatest affliction. Identifying stimuli that worsen asthma severity is an essential step to controlling both disease morbidity and the lessening economic impact. This study provides the first mechanistic investigation into how acute ethanol exposure will increase asthma severity in a murine model of mild cockroach allergen (CRA)-induced asthma. Outbred mice were sensitized to induce mild allergic asthma, with intratracheal CRA exposures on days 0 and 14. On day 21 mice were gavaged with water or 32% ethanol, and the third allergen exposure was given 30 min post-gavage. Asthmatic responses were measured at several time-points up to 42 h after the third allergen challenge. Ethanol-gavaged mice showed increased asthma severity within 90 min post-allergen challenge, with exacerbations lasting for 24 h. Ethanol caused greater airways obstruction, including an eightfold increase in epithelial cell mucin and increased mucus plugs, resulting in a 50% reduction in bronchiole patency. Ethanol gavage also induced significant increases in airways hyperreactivity. While T helper type 1 (Th1) and Th2 cytokines were not altered by ethanol gavage, pulmonary neutrophil and eosinophil recruitment were augmented. This increase was associated with increased chemokine production. Administration 2 h prior to ethanol gavage of a neutralizing antibody cocktail to keratinocyte-derived chemokine, macrophage inflammatory protein-2, eotaxin-1 and eotaxin-2 prevented ethanol-induced eosinophil recruitment and airways hyperreactivity. These data provide evidence that acute alcohol exposure immediately prior to a mild allergen-triggered asthmatic episode will exacerbate asthma severity mediated by increased production of chemokines.
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Bouchard
authors.forename: D R
authors.initials: DR
authors.lastname: Beal
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.forename: L J
authors.initials: LJ
authors.lastname: Vaickus
authors.forename: D G
authors.initials: DG
authors.lastname: Remick
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D054413:Chemokine CCL11 / Q000276:immunology; D054423:Chemokine CCL24 / Q000276:immunology; D054426:Chemokine CXCL2 / Q000276:immunology; D018925:Chemokines / Q000276:immunology; D003058:Cockroaches / Q000276:immunology*; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D019476:Insect Proteins / Q000276:immunology*; D051379:Mice; D008813:Mice, Inbred ICR; D009077:Mucins / Q000096:biosynthesis / Q000187:drug effects; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; C515457:Ccl11 protein, mouse; C515485:Ccl24 protein, mouse; D054413:Chemokine CCL11; D054423:Chemokine CCL24; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D019476:Insect Proteins; D009077:Mucins; C074302:keratinocyte-derived chemokines; D000431:Ethanol