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

• Published in: Mediators of Inflammation 2014-01, Vol.2014 (4), p.79-88
• Main Authors: Masid-de-Brito, Daniela, Queto, Tulio, Gaspar-Elsas, Maria Ignez C, Xavier-Elsas, Pedro
• Format: Article
• Language: English
• Subjects: Allergens; Allergens - administration & dosage; Allergies; Animals; Arachidonate 5-Lipoxygenase - deficiency; Arachidonate 5-Lipoxygenase - genetics; Arachidonate 5-Lipoxygenase - metabolism; Asthma; Asthma - immunology; Asthma - metabolism; Asthma - prevention & control; Cytokines; Diethylcarbamazine - pharmacology; Disease Models, Animal; Eosinophils - drug effects; Eosinophils - immunology; Hematology; Hematopoiesis - drug effects; Hematopoiesis - immunology; Indoles - pharmacology; Inflammation; Leukotrienes - biosynthesis; Mice; Mice, 129 Strain; Mice, Inbred BALB C; Mice, Knockout; Nonsteroidal anti-inflammatory drugs; Ovalbumin - administration & dosage; Ovalbumin - immunology; Receptors, Leukotriene - drug effects; Receptors, Leukotriene - metabolism; Signal Transduction - drug effects; Spleen
• ISSN: 0962-9351; 1466-1861
• DOI: 10.1155/2014/403970

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.