Leukotriene C4 induces bronchoconstriction and airway vascular hyperpermeability via the cysteinyl leukotriene receptor 2 in S-hexyl glutathione-treated guinea pigs

Abstract Cysteinyl leukotrienes act through G-protein-coupled receptors termed cysteinyl leukotriene 1 (CysLT 1 ) and cysteinyl leukotriene 2 (CysLT 2 ) receptors. However, little is known about the pathophysiological role of CysLT 2 receptors in asthma. To elucidate the possible involvement of CysLT 2 receptors in bronchoconstriction and airway vascular hyperpermeability, we have established a novel guinea pig model of asthma. In vitro study confirmed that CHO-K1 cells, expressing guinea pig CysLT 2 and CysLT 1 receptors are selectively stimulated by LTC 4 and LTD 4 , respectively. However, when LTC 4 was intravenously injected to guinea pigs, the resulting bronchoconstriction was fully abrogated by montelukast, a CysLT 1 receptor antagonist, indicating rapid metabolism of LTC 4 to LTD 4 in the lung. We found that treatment with S-hexyl glutathione (S-hexyl GSH), an inhibitor of gamma-glutamyl transpeptidase, significantly increased LTC 4 content and LTC 4 /(LTD 4 plus LTE 4 ) ratio in the lung. Under these circumstances, LTC 4 -induced bronchoconstriction became resistant to montelukast, but sensitive to Compound A, a CysLT 2 receptor antagonist, depending on the dose of S-hexyl GSH. Combination with montelukast and Compound A completely abrogated this spasmogenic response. Additionally, we confirmed that LTC 4 elicits airway vascular hyperpermeability via CysLT 2 receptors in the presence of high dose of S-hexyl GSH as evidenced by complete inhibition of LTC 4 -induced hyperpermeability by Compound A, but not montelukast. These results suggest that CysLT 2 receptors mediate bronchoconstriction and airway vascular hyperpermeability in guinea pigs and that the animal model used in this study may be useful to elucidate the functional role of CysLT 2 receptors in various diseases, including asthma.