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.

Eosinophil cationic protein mRNA expression in children with bronchial asthma

“…Previous studies have revealed that, in addition to infections caused by bacteria, viruses, and mycoplasma, environmental and genetic factors also play an important role in pathogenesis (Masid-de-Brito et al, 2014;Namjou et al, 2014;Martineau et al, 2015). Airway obstruction caused by bronchial asthma is reversible, while airway hyper-responsiveness and stimulation caused by inflammatory mediators are characteristic of bronchial asthma (Schoepf and Heun, 2014;Lozano et al, 2014;Gadhe, 2015;López-Expósito et al, 2015;Turner et al, 2015).…”

Diethylcarbamazine citrate ameliorates insulin resistance in high-fat diet-induced obese mice via modulation of adipose tissue inflammation

“…The ability of DEC to reduce murine lung inflammation was found largely dependent on 5-lipooxygenase inhibition and leukotriene products [12,33]. Furthermore, leukotrienes have been found very essential as inflammatory mediators in mediating HFD induced insulin resistance [34].…”

“…Hence, leukotriene inhibitors could reduce the levels of TNF-α, IL-6 and MCP-1. The inhibition of leukotriene production was linked to the reduced COX activity since DEC has been known as an inhibitor for AA metabolism which leads to both 5-LO and COX pathways [33].…”

α‐Galactosylceramide suppresses murine eosinophil production through interferon‐γ‐dependent induction ofNOsynthase andCD95

“…We had previously characterized (Jones et al ., ; Gaspar‐Elsas et al ., ; Queto et al ., ) a proapoptotic mechanism for regulation of eosinophil production, dependent upon iNOS and the ligand for CD95/Fas (CD95L/FasL), which operates in vivo during airway allergen challenge of sensitized mice, and accounts for the therapeutic effect of diethylcarbamazine (DEC), a leukotriene synthesis inhibitor (Matthews and Murphy, ), in experimental asthma (Queto et al ., ). Although activation of this mechanism by DEC and other drugs (de Luca et al ., ) prevents the induction of eosinophilia by allergen (Masid‐de‐Brito et al ., ), its blockade by LTD 4 and non‐steroidal anti‐inflammatory drugs (NSAIDs) (Xavier‐Elsas et al ., ) protects developing eosinophils from apoptosis. Furthermore, dexamethasone protects developing eosinophils from apoptosis by preventing expression of iNOS (de Luca et al ., ).…”