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

Abstract

CysLT₁ receptors are known to be involved in the pathogenesis of asthma. However, the functional roles of CysLT₂ receptors in this condition have not been determined. The purpose of this study is to develop an experimental model of CysLT₂ 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 γ-glutamyltranspeptidase (γ-GTP) under physiological conditions, S-hexyl GSH was used as a γ-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 CysLT₁ receptor antagonist, but not by BayCysLT₂RA, a CysLT₂ receptor antagonist. The inhibitory effect of montelukast was diminished by treatment with S-hexyl GSH, whereas the effect of BayCysLT₂RA 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 BayCysLT₂RA resulted in complete suppression of this air-trapping. Furthermore, BayCysLT₂RA completely suppressed LTC₄-induced airway vascular hyperpermeability. In conclusion, we found in this study that CysLT₂ receptors mediate LTC₄-induced bronchoconstriction and air-trapping in S-hexyl GSH-treated guinea pigs. It is therefore believed that CysLT₂ receptors contribute to asthmatic response involving air-trapping.

Keywords: Air-trapping; Asthma; Bronchoconstriction; CysLT(1) receptors; CysLT(2) receptors; Cysteinyl leukotrienes.