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  • It has been reported that CysLT

    2020-09-24

    It has been reported that CysLT2 receptors negatively regulate CysLT1 receptor-mediated response in allergic airway inflammation in mice. Knockdown of CysLT2 receptors augmented CysLT1 receptor-mediated mast cell proliferation [31] and eosinophilic airway inflammation induced by antigen challenge in Dermatophagoides farina-sensitized mice [32]. In addition, it is reported that CysLT2 receptor knockdown amplifies CysLT-induced ear thickness in mice [33]. In contrast, in the present study, such findings were not observed in S-hexyl GSH-treated guinea pigs. Although the reasons for this discrepancy is unknown, differences in species, tissues or cells used, or difference in methodology between systemic gene deficiency and receptor antagonism might be considered as the cause. In conclusion, we developed a new CysLT1 and CysLT2 receptors-mediated BMH-21 guinea pig model that can be useful for screening both CysLT2 receptor and CysLT1/2 receptor antagonists. In addition, we have shown that the dual CysLT1/2 receptor antagonist ONO-6950 can exert protective effect against anaphylactic response or asthma exacerbation. To further clarify the role of CysLT2 receptors in asthma, experiments using this novel model or clinical studies with CysLT2 receptors or CysLT1/2 dual antagonists are required.
    Introduction Cysteinyl leukotrienes (CysLTs: LTC4, LTD4 and LTE4) are inflammatory lipid mediators that elicit various pathophysiological events, including bronchoconstriction, vascular hyperpermeability, mucus secretion, and inflammatory cells influx (Liu and Yokomizo, 2015) via activation of CysLT1 receptors. Accordingly, a number of CysLT1 receptor antagonists are currently used for treatment of asthma (Choby and Lee, 2015). CysLT2 receptors are known to be expressed in the bronchial epithelium, smooth muscles, and on leukocytes (Heise et al., 2000, Corrigan et al., 2005, Mita et al., 2001). BMH-21 In addition, we have previously reported that both CysLT1 and CysLT2 receptors are expressed in airway tissues isolated from bronchial asthma subjects (Sekioka et al., 2015). Thus, activation of CysLT2 receptors is expected to contribute to the pathogenesis of asthma. Asthmatic airway obstruction is characterized by increased expiratory resistance, which elicits airways narrowing by bronchospasm, mucosal edema, mucus hypersecretion, and other inflammatory changes (DeGiorgi and White, 2008). Severe airflow obstruction in asthma patients is closely associated with insufficient expiration from the lungs, leading to air-trapping in the alveoli (DeGiorgi and White, 2008). This air-trapping may be mediated via CysLTs, considering the pathophysiological functions of these cysteinyl leukotrienes. Indeed, montelukast, a CysLT1 receptor antagonist, has been reported to improve regional air-trapping due to small airway obstruction in asthma patients (Zeidler et al., 2006). However, it has been unclear whether asthma-associated air-trapping can be effectively treated with CysLT1 receptor antagonists. As for CysLT2 receptors, their role in asthma air-trapping has so far not been clarified. Guinea pigs have been used as experimental animals for the development of LT modifiers, because their airway smooth muscles respond well to CysLTs. In guinea pigs, CysLT2 receptors are mainly activated by LTC4, whereas LTD4 is known to potently activate CysLT1 receptors (Ito et al., 2008). In humans, on the other hand, LTC4 and LTD4 are reported to have similar binding affinity for human CysLT2 receptors (Nothacker et al., 2000). Because LTC4 is rapidly metabolized to LTD4 by γ-glutamyl transpeptidase (γ-GTP) (Orning and Hammarström, 1980, Synder et al., 1984), LTC4-induced bronchoconstriction in guinea pigs is preferentially mediated via CysLT1 receptors. Thus, in order to make an animal model with asthmatic response mediated via CysLT2 receptors, a number of γ-GTP inhibitors have been used to minimize LTC4 metabolism to LTD4 (Bäck et al., 2001). We have recently reported that pre-treatment with S-hexyl GSH, a synthetic substrate of γ-GTP, in guinea pigs promotes LTC4- or antigen-induced bronchoconstriction and/or airway vascular hyperpermeability via both CysLT1 and CysLT2 receptors (Yonetomi et al., 2015a, Yonetomi et al., 2015b).