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  • It is well known that

    2020-11-19

    It is well known that CysLTs exert potent contractile action on human bronchial smooth muscles through activation of CysLT1 receptors. Indeed, in vitro antigen-induced contraction of passively sensitized human bronchial tissue is markedly suppressed by a pre-treatment with CysLT1 receptor antagonists.4, 15, 16 However, although CysLT2 receptors are also expressed in bronchial smooth muscles, their functional role in bronchial contraction has not been clarified. In this study, we evaluated CysLT receptors expression and effects of ONO-6950, dual CysLT1/2 antagonists and BayCysLT2RA, a CysLT2 receptor-specific antagonist on antigen-induced bronchoconstriction using isolated lung tissues from both peptide yy and non-asthma subjects.
    Methods
    Results
    Discussion In the present study, we showed that CysLT1 receptors were expressed on the bronchial smooth muscle and epithelium, and on alveolar leukocytes in all non-asthma and asthma subjects. On the other hand, CysLT2 receptors were expressed on these airway cells in 2 in 2 asthma subjects, whereas they were detected in only a part of non-asthma subjects. Furthermore, our results show that blockage of CysLT2 receptors suppressed antigen-induced bronchial smooth muscle contractions in lung tissue preparations from one of the two asthma subjects. One of the limitations of our study is that we were only able to use 2 asthma samples. It is quite difficult to obtain sufficient lung tissues from asthma patients for research. However, it should be noted that we used serial tissue sections that allowed co-expression of CysLT2 and CysLT1 receptors at the same sites. To our knowledge, this is the first report demonstrating the concurrent expression of CysLT2 receptors with CysLT1 receptors in airway tissues of actual asthma subjects compared to non-asthma subjects. In addition, our findings suggest that CysLT2 receptors are functionally involved in asthma bronchoconstriction. It is also interesting to note that the asthma subjects recruited in this study had mild symptoms compared to those of the so-called “severe asthma”, since asthma subject 1 and 2 were classified as “mild persistent” and “mild intermittent”, and were treated with a medium dose ICS (treatment step 2) and a low dose ICS (treatment step 1), respectively. It may therefore be speculated that expression of CysLT2 receptors is further up-regulated in subjects with severe asthma or asthma exacerbation. Indeed, it is reported that asthma exacerbation triggers CysLT2 receptors expression in eosinophils, a phenomenon not observed during stable periods. On the other hand, Negri et al. have demonstrated that fluticasone inhibited IL-4-induced CysLT2 receptors protein expression, but not CysLT1 receptors, on monocytes, T cells, and eosinophils. Because the asthma subjects were treated with ICS/LABA, the CysLT2 receptors expression may had been negatively regulated. Regarding effect of LABA on CysLT receptors expression, there has been no study to our knowledge. In agreement with our results showing the presence of CysLT2 receptors in alveolar leukocytes, both CysLT1 and CysLT2 receptors have been reported to be expressed not only in macrophages, but also in eosinophils,19, 21 mast cells, basophils, and dendritic cells. The functional importance of CysLT2 receptors in these leukocytes was not addressed in this study. However, Jiang et al. have shown that both CysLT1 and CysLT2 receptors are expressed on the membranes and nuclei of a human mast cell line, and that knockdown of CysLT2 receptors increases CysLT1 receptors surface expression. These findings suggest that activation of CysLT2 receptors down-regulates CysLT1 receptors expression. In addition to CysLT2 receptors activation negative feedback on CysLT1 receptors expression, a broader functional regulation between CysLT1 and CysLT2 receptors has also been reported: Knockdown of CysLT2 receptors was reported to increase CysLT1 receptor-dependent proliferation of human mast cells. Barrett et al. have shown that D. farinae sensitization and challenge in CysLT2 receptor-deficient mice results in a marked increase in eosinophilic pulmonary inflammation, serum IgE level, and Th2 cytokine level. Maekawa et al. have also reported that leukotriene-induced ear edema shows a delayed peak response in CysLT2 receptor-deficient mice compared to wild-type mice. These findings suggest that activation of CysLT2 receptors down-regulates not only CysLT1 receptors expression, but also CysLT1 receptor-mediated biological and inflammatory responses. However, as shown in this study, treatment with the CysLT2 receptor antagonist BayCysLT2RA did not reverse montelukast-induced inhibition of anaphylactic bronchoconstriction in specimens from both the non-asthma and asthma subjects. Therefore, CysLT1 receptors activation may be differently regulated by CysLT2 receptors expression, at least in human bronchial contractions. Alternatively, the observed discrepancy may be due to species difference.