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  • The purposes of this study is to develop an experimental


    The purposes of this study is to develop an experimental model of CysLT2 receptor-mediated LTC4-induced lung air-trapping in guinea pigs using S-hexyl GSH, and to clarify the mechanism underlying response to such trapping using montelukast, a CysLT1 receptor antagonist, BayCysLT2RA, a CysLT2 receptor antagonist, and salmeterol, a Aminoallyl-UTP bronchodilatory adrenergic β2 agonist.
    Materials and methods
    Discussion In this study, we developed an experimental model of CysLT2 receptor-mediated air-trapping in the lung by exposure to LTC4 in S-hexyl GSH-treated guinea pigs. The CysLT2 receptor-mediated air-trapping involves adrenergic β2 agonist-resistant mechanism. It has been well known that CysLTs are important lipid mediators, which are elevated in large amounts in the blood and lung tissues after allergen challenge in bronchial Aminoallyl-UTP patients (Dahlén et al., 1983, Hansson et al., 1983, Sasagawa et al., 1994, Wenzel et al., 1990). In addition, we have reported that CysLT2 receptors are expressed in airway tissues isolated from bronchial asthma subjects (Sekioka et al., 2015). Thus, the present experimental results suggest the possibility that CysLTs can cause air-trapping via activation of CysLT2 receptors in the pathogenesis of bronchial asthma of humans. Consistent with the results of our previous report (Yonetomi et al., 2015a), single dose of S-hexyl GSH (60mg/kg) promoted CysLT2 receptor-mediated LTC4-induced bronchoconstriction by inhibition of LTC4 conversion to LTD4 in anesthetized artificially ventilated guinea pigs. However, under these experimental conditions, bronchoconstriction can be considered to reflect increased pressure similar to that induced by a ventilator (Konzett and Rössler, 1940), which is not relevant to expiratory dyspnea, a typical airway obstruction at asthma attack (DeGiorgi and White, 2008). Thus, in the next experiments of this study, conscious, spontaneously breathing guinea pigs were exposed to LTC4 mist, and the increase in sRaw was measured as index of expiratory dyspnea (Pennock et al., 1979). In this model, LTC4 induced CysLT2-mediated increases in sRaw in guinea pigs treated with S-hexyl GSH. In addition to the increase in sRaw, LTC4 enlarged whole lung volume, indicating air-trapping in the lung. Because air-trapping has been suggested to be related to small airway obstruction (Contoli et al., 2012, Sorkness et al., 2008, Hartley et al., 2016), activation of CysLT2 receptors may contribute to small airway obstruction. As far as we know, this is the first report showing that CysLT2 receptors contribute to air-trapping in the lung of guinea pigs. Because bronchoconstriction is one of the causes of air-trapping, we comparatively evaluated the effect of an adrenergic β2 receptor 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.