Corticosteroids and adrenergic receptor agonists have been c

Corticosteroids and adrenergic β2 receptor agonists have been clinically used as effective pharmacotherapy for asthma. In this study, asthmatic response in both S-hexyl GSH-non-treated and treated animals was attenuated by single treatment with dexamethasone or salmeterol. Combination treatment with these two agents completely suppressed asthmatic response. Therefore, the effectiveness of dexamethasone and salmeterol against asthmatic response suggests that the anaphylactic model used could reproduce clinical settings. In addition, asthmatic response under treatment with S-hexyl GSH generally be to screen for anti-asthma drugs. 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 SU 9516 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). 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.