It is now widely known
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 Pyridoxal isonicotinoyl hydrazone mg 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.
Henderson et al. have demonstrated that montelukast blockade of CysLT1 receptors improves airway remodeling, including airway goblet cell metaplasia, smooth muscle cell layer thickening, and subepithelial fibrosis in a mouse model of asthma. The histological findings of this study revealed a thickened bronchial epithelium exhibiting epithelial cells filled with AB/PAS-positive mucus in the specimens prepared from the asthma patients. Interestingly, in these specimens, CysLT1 receptors tended to be expressed on the mucus-positive epithelium, suggesting that CysLT1 receptors activation is involved in the development of epithelial remodeling in humans as reported in mice. It has also been reported that CysLTs mediate Th2 cell-dependent pulmonary inflammation through activation of CysLT1 receptors in mice.27, 28 Considering the fact that both CysLT2 and CysLT1 receptors are highly expressed in the airway epithelium, it is possible that CysLT2 receptors also play a role in the development of airway remodeling. This hypothesis need to be further investigated both in vitro and in vivo.
In conclusion, we have shown in this study that CysLT2 receptors were expressed in lung specimens isolated from 2 asthma subjects. This CysLT2 receptors expression may contribute to antigen-induced bronchoconstriction in certain asthma cases. These results imply that CysLT2 receptor antagonists, including BayCysLT2RA and ONO-6950, may be useful for the treatment of the certain asthma population. However, because the present findings were led from only 2 asthma specimens, further preclinical and clinical studies on CysLT2-or CysLT1/2-receptor antagonists are required.
Introduction Microglia are the primary immune cells of the brain. They are rapidly activated in response to various pathological conditions such as infection, stroke or neurodegenerative processes. Increased production of proinflammatory cytokines by activated microglia contributes to microglia-related neurotoxicity in a series of neurodegenerative disorders, including Parkinson׳s disease (PD) (Glass et al., 2010, More et al., 2013, Nolan et al., 2013, Ramsey and Tansey, 2014). Inhibition or blockade of microglial activation was shown to attenuate nigrostriatal inflammation and to rescue dopaminergic neurons from degeneration in experimental PD (Glass et al., 2010, Ramsey and Tansey, 2014, Tansey and Goldberg, 2010). Therefore, identification of the molecules that modulate microglial activation and release of proinflammatory mediators may offer a potential therapeutic strategy for the treatment of PD.