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  • In agreement with our results showing the

    2020-07-30

    In agreement with our results showing the presence of CysLT2 receptors in alveolar leukocytes, integrin inhibitors 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 integrin inhibitors 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. It is now widely known that blockade of CysLT1 receptors strongly inhibits antigen-induced bronchial contractions in specimens isolated from non-asthma subjects. However, this blockade is not complete as shown in the present study and in other literature.4, 15, 16 The results of the current study suggest that CysLT2 receptors activation has no significant role in the bronchial contractions recorded in the non-asthma specimens. On the other hand, in one of the two asthma specimens, CysLT2 receptors blockade inhibited anaphylactic bronchoconstriction. This inhibition was potentiated by dual blockade of CysLT1 and CysLT2 receptors. These results suggest that there may be a certain asthma background, in which activation of CysLT2 receptors is involved in anaphylactic bronchocontractile response, and thus may play a significant role in asthma response in certain asthma population. It is not clear why the involvement of CysLT2 receptor activation in anaphylactic response was different between the 2 asthma specimens, even though CysLT2 receptors were expressed in both specimens to a similar degree. Mechanisms other than increased expression of CysLT2 receptors, such as functional up-regulation, may also be involved in this response. It is intriguing to speculate that asthma background affects such functional up-regulation. On the other hand, it should be noted that one lung sample showing CysLT2 receptors contribution to bronchoconstriction was derived from an asthma subject (asthma subject 1), who had had a history of atopy, whereas the other subject (asthma subject 2) had not. In addition, asthma subject 1 had a relatively high percentage of eosinophils in peripheral blood leukocytes (6.8%). Moreover, asthma subject 1 was non-smoker, whereas asthma subject 2 was smoker. It is therefore suggested that these subjects backgrounds may have affected the function of CysLT2 receptors. However, further studies are needed to clarify the exact role of CysLT2 receptors in asthma pathogenesis.