Concentration-Dependent Noncysteinyl Leukotriene Type 1 Receptor-Mediated Inhibitory Activity of Leukotriene Receptor Antagonists

摘要: The use of cysteinyl leukotriene receptor antagonists (LTRAs) for asthma therapy has been associated with a significant degree interpatient variability in response to treatment. Some that may be attributable noncysteinyl type 1 (CysLT )-mediated inhibitory mechanisms have demonstrated this group drugs. We used model CysLT signaling human monocytes characterize -dependent and -independent anti-inflammatory activity two chemically different, clinically relevant LTRAs (montelukast zafirlukast). Using receptor-desensitization experiments -transfected HEK293 cells IL-10– small interfering RNA-induced downregulation expression, we showed reported agonists D 4 UDP signal through calcium mobilization, acting on separate receptors, both pathways were inhibited by montelukast zafirlukast. However, 3-log greater concentrations required the inhibition UDP-induced signaling. In monocytes, UDP, but not , induced IL-8 production was significantly drugs at micromolar concentrations. At low concentrations, also ionophore-induced (leukotriene B C ) production, indicating 5-lipoxygenase activities. report herein zafirlukast, concentration-dependent manner, can inhibit non–CysLT -mediated proinflammatory reactions, suggesting activities potentially Higher doses currently known or new compounds derived from class represent strategy finding more efficient bronchial asthma.