title: Roles of 5-lipoxygenase and cysteinyl-leukotriene type 1 receptors in the hematological response to allergen challenge and its prevention by diethylcarbamazine in a murine model of asthma.
abstract: Diethylcarbamazine (DEC), which blocks leukotriene production, abolishes the challenge-induced increase in eosinopoiesis in bone-marrow from ovalbumin- (OVA-) sensitized mice, suggesting that 5-lipoxygenase (5-LO) products contribute to the hematological responses in experimental asthma models. We explored the relationship between 5-LO, central and peripheral eosinophilia, and effectiveness of DEC, using PAS or BALB/c mice and 5-LO-deficient mutants. We quantified eosinophil numbers in freshly harvested or cultured bone-marrow, peritoneal lavage fluid, and spleen, with or without administration of leukotriene generation inhibitors (DEC and MK886) and cisteinyl-leukotriene type I receptor antagonist (montelukast). The increase in eosinophil numbers in bone-marrow, observed in sensitized/challenged wild-type mice, was abolished by MK886 and DEC pretreatment. In ALOX mutants, by contrast, there was no increase in bone-marrow eosinophil counts, nor in eosinophil production in culture, in response to sensitization/challenge. In sensitized/challenged ALOX mice, challenge-induced migration of eosinophils to the peritoneal cavity was significantly reduced relative to the wild-type PAS controls. DEC was ineffective in ALOX mice, as expected from a mechanism of action dependent on 5-LO. In BALB/c mice, challenge significantly increased spleen eosinophil numbers and DEC treatment prevented this increase. Overall, 5-LO appears as indispensable to the systemic hematological response to allergen challenge, as well as to the effectiveness of DEC.
authors.affiliation: Departamento de Imunologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, 21.941-590 Rio de Janeiro, RJ, Brazil.
authors.forename: Daniela
authors.initials: D
authors.lastname: Masid-de-Brito
authors.affiliation: Departamento de Pediatria, Instituto Nacional de Saúde da Mulher, da Criancça e do Adolescente Fernandes Figueira, FIOCRUZ, 22.250-020 Rio de Janeiro, RJ, Brazil.
authors.forename: Túlio
authors.initials: T
authors.lastname: Queto
authors.affiliation: Departamento de Pediatria, Instituto Nacional de Saúde da Mulher, da Criancça e do Adolescente Fernandes Figueira, FIOCRUZ, 22.250-020 Rio de Janeiro, RJ, Brazil.
authors.forename: Maria Ignez C
authors.initials: MI
authors.lastname: Gaspar-Elsas
authors.affiliation: Departamento de Imunologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, 21.941-590 Rio de Janeiro, RJ, Brazil.
authors.forename: Pedro
authors.identifier: 0000-0003-3057-6062
authors.initials: P
authors.lastname: Xavier-Elsas
mesh_terms: D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001249:Asthma / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control*; D004049:Diethylcarbamazine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D006410:Hematopoiesis / Q000187:drug effects / Q000276:immunology; D007211:Indoles / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D018077:Receptors, Leukotriene / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D002722:Chlorobenzenes
chemical_list: D000485:Allergens; D001094:Arachidonate 5-Lipoxygenase; D004049:Diethylcarbamazine; D007211:Indoles; D015289:Leukotrienes; D010047:Ovalbumin; D018077:Receptors, Leukotriene; C060893:MK-886; D002722:Chlorobenzenes; C083169:leukotriene D4 receptor