Masid-de-Brito Daniela, Queto Túlio, Gaspar-Elsas Maria Ignez C, Xavier-Elsas Pedro
Departamento de Imunologia, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, 21.941-590 Rio de Janeiro, RJ, Brazil.
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.
Mediators Inflamm. 2014;2014:403970. doi: 10.1155/2014/403970. Epub 2014 Nov 11.
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.
乙胺嗪(DEC)可阻断白三烯的产生,消除卵清蛋白(OVA)致敏小鼠骨髓中激发诱导的嗜酸性粒细胞生成增加,这表明5-脂氧合酶(5-LO)产物参与了实验性哮喘模型中的血液学反应。我们使用PAS或BALB/c小鼠以及5-LO缺陷突变体,探讨了5-LO、中枢和外周嗜酸性粒细胞增多以及DEC有效性之间的关系。我们对新鲜收获或培养的骨髓、腹腔灌洗液和脾脏中的嗜酸性粒细胞数量进行了定量,无论是否给予白三烯生成抑制剂(DEC和MK886)以及半胱氨酰白三烯I型受体拮抗剂(孟鲁司特)。在致敏/激发的野生型小鼠中观察到的骨髓嗜酸性粒细胞数量增加,通过MK886和DEC预处理得以消除。相比之下,在ALOX突变体中,对致敏/激发的反应中,骨髓嗜酸性粒细胞计数以及培养中的嗜酸性粒细胞生成均未增加。在致敏/激发的ALOX小鼠中,激发诱导的嗜酸性粒细胞向腹腔的迁移相对于野生型PAS对照显著减少。正如从依赖于5-LO的作用机制所预期的那样,DEC在ALOX小鼠中无效。在BALB/c小鼠中,激发显著增加了脾脏嗜酸性粒细胞数量,而DEC治疗可防止这种增加。总体而言,5-LO似乎对于过敏原激发的全身血液学反应以及DEC的有效性不可或缺。