CysLT2 receptor activation is involved in LTC4-induced lung air- trapping in guinea pigs

CysLT(1) receptors are known to be involved in the pathogenesis of asthma. However, the functional roles of CysLT(2) receptors in this condition have not been determined. The purpose of this study is to develop an experimental model of CysLT(2) receptor-mediated LTC4-induced lung air-trapping in guinea pigs and use this model to clarify the mechanism underlying response to such trapping. Because LTC4 is rapidly converted to LTD4 by gamma-glutamyltranspeptidase (gamma-GTP) under physiological conditions, S-hexyl GSH was used as a gamma-GTP inhibitor. In anesthetized artificially ventilated guinea pigs with no S-hexyl GSH treatment, i.v. LTC4-induced bronchoconstriction was almost completely inhibited by montelukast, a CysLT(1) receptor antagonist, but not by BayCysLT(2)RA, a CysLT(2) receptor antagonist. The inhibitory effect of montelukast was diminished by treatment with S-hexyl GSH, whereas the effect of BayCysLT(2)RA was enhanced with increasing dose of S-hexyl GSH. Macroscopic and histological examination of lung tissue isolated from LTC4-/S-hexyl-GSH-treated guinea pigs revealed air-trapping expansion, particularly at the alveolar site. Inhaled LTC4 in conscious guinea pigs treated with S-hexyl GSH increased both airway resistance and airway hyperinflation. On the other hand, LTC4-induced air-trapping was only partially suppressed by treatment with the bronchodilator salmeterol. Although montelukast inhibition of LTC4-induced air-trapping was weak, treatment with BayCysLT(2)RA resulted in complete suppression of this air-trapping. Furthermore, BayCysLT(2)RA completely suppressed LTC4-induced airway vascular hyperpermeability. In conclusion, we found in this study that CysLT(2) receptors mediate LTC(4)induced bronchoconstriction and air-trapping in S-hexyl GSH-treated guinea pigs. It is therefore believed that CysLT(2) receptors contribute to asthmatic response involving air-trapping.