On the other hand p responds to
On the other hand, p38 responds to environmental stress, including ultraviolet light, heat, osmotic shock, and inflammatory cytokines (Pearson et al., 2001, Kumar et al., 2003), and is activated in astrocytes after ischemia-like injury (Yung and Tolkovsky, 2003, Niu et al., 2009). Moreover, p38 activation mediates the increased AQP4 and AQP9 expression induced by hyperosmolar mannitol (Arima et al., 2003). Thus, p38 activation may be an important regulation mechanism in CysLT2 receptor-mediated AQP4 up-regulation in ischemic astrocytes. However, the signaling pathways in this process might be complex because many more changes in signaling molecules and their interactions occur after ischemic astrocyte injury (Mehta et al., 2007, Takano et al., 2009, Rossi et al., 2007).
In summary, we found that CysLT2 receptors mediate ischemic astrocyte injury partly through AQP4 up-regulation; this may be mediated throughout the ERK1/2 and p38 MAPK signaling pathways. Since astrocytes play protective roles in ischemic neuron injury, astrocyte injury after severe ischemia may exacerbate neuronal injury and neurological outcomes (Mehta et al., 2007, Takano et al., 2009, Rossi et al., 2007). Therefore, it is necessary to elucidate how CysLT2 receptor-mediated ischemic astrocyte injury is associated with neuronal injury and neurological outcomes in further studies.
Conclusion The present study showed that CysLT2 receptors mediate ischemic astrocyte injury partly through AQP4 up-regulation; this may be mediated throughout the ERK1/2 and p38 MAPK signaling pathways.
Conflict of interest statement
Acknowledgements This study was supported by National Natural Science Foundation of China, Nos. 30672449, 30772561, 30801397 and 30873053. We thank Dr. T. Jon Seiders (Amira Pharmaceuticals, USA) for providing sample of Bay cysLT2, and Dr. IC Bruce for critically reading and revising this manuscript.
Introduction Leukotrienes are inflammatory mediators derived from the arachidonic SR 8278 clinical and divided by structure into two groups: cysteinyl leukotriene (cysLT) and dihydroxy leukotriene. Cysteinyl leukotrienes, i.e. leukotriene C4 (LTC4), LTD4, and LTE4, are produced by granulocytes (eosinophils, basophils), macrophages and mast cells, whereas the dihydroxy leukotriene LTB4 is produced by granulocytes (eosinophils, neutrophils) and macrophages (Brink et al., 2003, Kanaoka and Boyce, 2004, Capra et al., 2007). Cysteinyl leukotrienes are implicated in respiratory inflammatory diseases, such as asthma and allergic rhinitis, as well as cardiovascular, gastrointestinal and skin inflammatory disorders, including atherosclerotic cardiovascular disease, eosinophilic gastroenteritis and atopic eczema (Brink et al., 2003, Kanaoka and Boyce, 2004, Capra et al., 2007, Riccioni et al., 2010). Two subtypes of cysteinyl leukotriene receptors (CysLT), i.e. CysLT1 and CysLT2, have been cloned and characterized (Lynch et al., 1999, Sarau et al., 1999, Nothacker et al., 2000). The rank order of agonist potency at the CysLT1 receptor is LTC4=LTD4>LTE4 or LTC4=LTD4=LTE4, whereas the rank order of agonist potency at the CysLT2 receptor is LTC4=LTD4>>LTE4 (Bäck, 2002). Many potent and selective CysLT1 receptor antagonists, including montelukast, zafirlukast, pranlukast and pobilukast, have been developed. They block cysLT-induced calcium mobilization in CysLT1 but not CysLT2 transfected cells (Takasaki et al., 2000, Snyder and Krell, 1986). On the other hand, only two selective CysLT2 receptor antagonists, Bay cysLT2 and HAMI3379, have been reported to date (Huang et al., 2008, Wunder et al., 2010). Another CysLT2 antagonist, BAY u9773, is a dual CysLT1 and CysLT2 antagonist (Bäck, 2002). Both CysLT1 and CysLT2 receptors are expressed in the gastrointestinal system. CysLT1 receptors are expressed in the small intestine, colon and liver, whereas CysLT2 receptors are found in the stomach, small intestine, colon, liver and pancreas (Brink et al., 2003, Kanaoka and Boyce, 2004, Capra et al., 2007, Bäck, 2002, Heise et al., 2000). Previous studies demonstrated that cysteinyl leukotrienes cause contraction of the esophagus (Chang et al., 2008, Kim et al., 1998), lower esophageal sphincter (Huang, 2009, Kim et al., 1998), stomach (Goldenberg and Subers, 1983, Miura et al., 1992, Miyata et al., 1995), ileum (Bäck et al., 1996), colon (Ieiri et al., 2001) and gallbladder (Falcone and Krell, 1992, Freedman et al., 1993) as well as relaxation in the internal anal sphincter (de Godoy et al., 2009). The cysteinyl leukotriene-induced contractions are mediated by CysLT1 receptors in the esophagus, lower esophageal sphincter and gallbladder (Falcone and Krell, 1992, Freedman et al., 1993, Chang et al., 2008, Huang, 2009). On the other hand, the cysteinyl leukotriene-induced contraction is mediated by CysLT2 receptors in the ileum (Bäck et al., 1996). The subtype of the cysteinyl leukotriene receptor mediating the cysteinyl leukotriene-induced relaxation of internal anal sphincter is not clear (de Godoy et al., 2009).