Because bronchoconstriction is one of the causes

Because bronchoconstriction is one of the causes of air-trapping, we comparatively evaluated the effect of an adrenergic β2 interleukin 1 receptor antagonist agonist on LTC4- and LTD4-induced asthmatic responses in guinea pigs. Inhaled LTC4-induced increase in sRaw and airway hyperinflation in S-hexyl GSH-treated guinea pigs was significantly suppressed by treatment with salmeterol, although this suppression was not complete. On the contrary, inhaled LTD4-induced increase in sRaw and airway hyperinflation was completely suppressed by this bronchodilatory adrenergic β2 agonist. These results suggest that unlike LTD4-induced CysLT1 receptor-mediated responses, LTC4-induced CysLT2 receptor-mediated responses are mediated not only via airway smooth muscle constriction, but also via other functional changes. Both LTC4 and LTD4 induce airway vascular hyperpermeability through activation of CysLT1 receptors (Bochnowicz and Underwood, 1995, Hua et al., 1985, Woodward et al., 1983a, Woodward et al., 1983b). In addition, we recently found that CysLT2 receptors were also involved in the CysLT-induced airway vascular hyperpermeability (Yonetomi et al., 2015a). It has also been reported that LTC4-induced vascular permeability in ear was enhanced in human CysLT2 receptor-transgenic mice compared to that in wild type mice (Hui et al., 2004). LTD4-induced vascular hyperpermeability in guinea pigs was not inhibited by a β2-agonist salbutamol (Woodward et al.,. 1984). On the other hand, the effect of a β2-agonist on LTC4-induced vascular hyperpermeability has been unclear. In the present study, we found that i.v. LTC4-induced airway vascular hyperpermeability in S-hexyl-GSH-treated guinea pigs was completely suppressed by BayCysLT2RA, but not by montelukast Taken together, these findings suggest that the bronchodilator-resistant increase in sRaw and airway hyperinflation induced by LTC4 were elicited by both bronchoconstriction and mucosal edema via activation of CysLT2 receptors. Air-trapping at the small airways is related to severe asthma (Bjermer, 2014), and acute exacerbation (Mahut et al., 2010). Although asthma patients are generally treated with inhaled corticosteroid (ICS) or with ICS and long-acting β2 agonist (LABA), the efficacy of such treatment depends on drug particle size, as large particulates cannot be delivered to small airways (Barnes et al., 2011, Busse et al., 1999, Papi et al., 2007, Price et al., 2013). However, oral dosing can distribute a drug to small airway tissues via blood circulation. Actually, CysLT1 receptor antagonists, such as pranlukast and montelukast have been reported to be effective against air-trapping or small airway inflammation in bronchial asthma (Nakaji et al., 2013, Yasui et al., 2012, Zeidler et al., 2006). However, CysLT1 receptor antagonists are reported to be ineffective in about half of asthma patients (Israel et al., 2002, Lima et al., 2006). If peripheral airway obstruction is one of the causes of poor response to CysLT1 receptor antagonists, oral CysLT2 and CysLT1/2 receptor antagonists are expected to be useful as asthma therapeutic agents.