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  • The CysLT receptor antagonist BayCysLT RA significantly supp

    2020-10-17

    The CysLT2 receptor antagonist BayCysLT2RA significantly suppressed multiple antigen challenge-induced infiltration of eosinophils and mononuclear Fmoc-Phe-OH into the lung, indicating that CysLT2 receptor activation is involved in leukocyte migration. In contrast to the present finding, Barret et al. [21] reported that antigen-induced eosinophilic pulmonary inflammation was markedly augmented in CysLT2 receptor-deficient mice. In addition, negative regulation of CysLT2 receptors in Th2-type pulmonary inflammation was induced by inhibiting both CysLT1 receptor signaling and expression [21]. An in vitro study suggested that CysLT2 receptors can negatively regulate CysLT1 receptor expression and LTD4-induced mitogenic responses in mast cells [36]. The difference between our results and the literature [21] may be because of different experimental tools, CysLT2 receptor antagonists, and CysLT2 receptor-deficient mice. We have confirmed that BayCysLT2RA lacked effects on other receptors associated with smooth muscle constriction or relaxation, such as adrenergic α2A, α2B and β2 receptors, histamine H1 and H2 receptors, and endothelin ETA and ETB receptors (unpublished data). Regarding pharmakokinetics, when BayCysLT2RA was i.v. administered at 0.3 and 1 mg/kg, t1/2 was approximately 0.3 h (unpublished data). Collectively, the effect of BayCysLT2RA is specific for CysLT2 receptors, but not so long-lasting. This situation of lowered function of CysLT2 receptors under the treatment with BayCysLT2RA should be different from that in CysLT2 receptor deficient mice, in which CysLT2 receptors congenitally defected. In gene knock out mice, however, other compensatory changes due to the gene modification should also be considered. On the other hand, inhibition by CysLT2 receptor antagonist was not dose-dependent from 0.03–0.3 mg/kg. Increasing the BayCysLT2RA dose to 1 and 3 mg/kg, did not further inhibit infiltration of eosinophils and mononuclear cells (data not shown). The absence of dose-dependency may be related to the regulatory functions of CysLT2 receptors as reported by others [21], [36], but we have not examined the effect of BayCysLT2RA on CysLT1 receptor expression. Flow cytometric analyses indicated that CysLT2 receptor-positive leukocytes included Siglec F+ cells (eosinophils), CD11c+ F4/80+ cells (alveolar macrophages), and CD11c+ I-A/I-E+ cells (conventional dendritic cells). Only a small percentage of Gr-1+ cells (neutrophils) was positive for CysLT2 receptors. Eosinophils, macrophages, and dendritic cells in humans express both CysLT1 and CysLT2 receptors [37], [38], [39], but whether these receptors are expressed in murine leukocytes has been unclear. Consistent with the expression profiles of CysLT2 receptors in the present study, CysLT2 receptor antagonists significantly inhibited both eosinophils and mononuclear cells (macrophages and dendritic cells), but not neutrophils. CysLT2 receptors expressed in eosinophils, alveolar macrophages, and dendritic cells may be directly related to pulmonary recruitment of these cells to the lung. The CysLT1 receptor antagonist montelukast effectively suppresses antigen-induced pulmonary eosinophilia [16], [17], [18], [19], [20], but montelukast did not significantly suppress airway eosinophila even at 1 mg/kg in our murine model. In this study, dose of montelukast was increased to 3 and 10 mg/kg, whereas the inhibitory effect on the eosinophilia was not augmented (data not shown). The difference between the literature [16], [17], [18], [19], [20], [21] and the present study may be due to a difference in antigen-challenging protocols. In our study, antigen challenge was conducted by intratracheal administration, but other studies used intranasal administration and inhalation of mist for antigen challenge [16], [17], [18], [19], [20], [21]. Intratracheal administration can efficiently deliver antigen to the lung, resulting in lung exposed to a large amount of antigen. In addition, drug resistance to the glucocorticoid dexamethasone was observed in our study. In murine models of pulmonary allergy, dexamethasone markedly suppresses antigen-induced pulmonary eosinophilia at less than 3 mg/kg [20], [40]. However, the inhibitory degree of airway eosinophila in our model by 3 mg/kg dexamethasone was less than 40%. The limited effects of glucocorticoid have been observed elsewhere [23], but the mechanisms underlying glucocorticoid resistance remain unclear. The effectiveness of BayCysLT2RA implied that blockade of CysLT2 receptors may be clinically effective for steroid-resistant asthma.