title: Blocking the leukotriene B4 receptor 1 inhibits late-phase airway responses in established disease.
abstract: Most of the studies investigating the effectiveness of blocking the leukotriene B4 (LTB4) receptor 1 (BLT1) have been performed in models of primary or acute allergen challenge. The role of the LTB4-BLT1 pathway in secondary challenge models, where airway hyperresponsiveness (AHR) and airway inflammation have been established, has not been defined. We investigated the effects of blocking BLT1 on early- and late-phase development of AHR and airway inflammation in previously sensitized and challenged mice. Female BALB/c mice were sensitized (Days 1 and 14) and challenged (primary, Days 28-30) with ovalbumin. On Day 72, mice were challenged (secondary) with a single OVA aerosol, and the early and late phases of AHR and inflammation were determined. Specific blockade of BLT1 was attained by oral administration of a BLT1 antagonist on Days 70 through 72. Administration of the antagonist inhibited the secondary ovalbumin challenge-induced alterations in airway responses during the late phase but not during the early phase, as demonstrated by decreases in AHR and in bronchoalveolar lavage neutrophilia and eosinophilia 6 and 48 hours after secondary challenge. The latter was associated with decreased levels of KC protein, macrophage inflammatory protein 2, and IL-17 in the airways. These data identify the importance of the LTB4-BLT1 pathway in the development of late-phase, allergen-induced airway responsiveness after secondary airway challenge in mice with established airway disease.
authors.affiliation: Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Waseda
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Miyahara
authors.forename: Arihiko
authors.initials: A
authors.lastname: Kanehiro
authors.forename: Genyo
authors.initials: G
authors.lastname: Ikeda
authors.forename: Hikari
authors.initials: H
authors.lastname: Koga
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Fuchimoto
authors.forename: Etsuko
authors.initials: E
authors.lastname: Kurimoto
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tanimoto
authors.forename: Mikio
authors.initials: M
authors.lastname: Kataoka
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D000906:Antibodies / Q000097:blood; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D054360:Chemokine CXCL1 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects; D010047:Ovalbumin; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000517:prevention & control; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
chemical_list: D018927:Anti-Asthmatic Agents; D000906:Antibodies; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D018836:Inflammation Mediators; D020381:Interleukin-17; D020024:Leukotriene Antagonists; C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; D010047:Ovalbumin