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  • These cytokines except for TGF can also


    These cytokines, except for TGF-β can also increase CysLT1R mRNA expression. We further demonstrated that TGF-β and IL-13 were able to increase the proliferation of human BSMC in response to LTD4. BSMC proliferation was CysLT1R-dependent, given that Montelukast ablated this effect. Taken together, our findings support a role for CysLT1R in the airway remodeling observed in asthma and may provide a rationale for preventive and therapeutic intervention at this level.
    Introduction Leukotrienes are inflammatory mediators derived from the arachidonic cytochalasin d 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). LTD4 and LTC4 cause contraction in the rat stomach and these contractions are sensitive to CysLT1 receptor antagonists (Goldenberg and Subers, 1983, Miura et al., 1992, Miyata et al., 1995). However, effects of other leukotrienes in the gastric contraction and inhibitory effects of potent, selective CysLT antagonists in the leukotriene-induced gastric contraction were not clearly known. The subtype of the cysteinyl leukotriene receptor mediating the leukotriene-induced contraction of stomach was not clear. The purpose of the present study is to characterize cysteinyl leukotriene receptors in the stomach mediating leukotriene-induced muscle contraction.