Air trapping at the small airways

Air-trapping at the small airways is related to severe Erastin receptor (Bjermer, 2014), and acute exacerbation (Mahut et al., 2010). Although asthma patients are generally treated with inhaled corticosteroid (ICS) or with ICS and long-acting β2 agonist (LABA), the efficacy of such treatment depends on drug particle size, as large particulates cannot be delivered to small airways (Barnes et al., 2011, Busse et al., 1999, Papi et al., 2007, Price et al., 2013). However, oral dosing can distribute a drug to small airway tissues via blood circulation. Actually, CysLT1 receptor antagonists, such as pranlukast and montelukast have been reported to be effective against air-trapping or small airway inflammation in bronchial asthma (Nakaji et al., 2013, Yasui et al., 2012, Zeidler et al., 2006). However, CysLT1 receptor antagonists are reported to be ineffective in about half of asthma patients (Israel et al., 2002, Lima et al., 2006). If peripheral airway obstruction is one of the causes of poor response to CysLT1 receptor antagonists, oral CysLT2 and CysLT1/2 receptor antagonists are expected to be useful as asthma therapeutic agents. Asthma pathogenesis involves not only acute airway obstruction, but also chronic eosinophilic airway inflammation including airway hyperresponsiveness. It is unclear whether antagonism of CysLT2 receptors would results in anti-inflammation in asthma patients. Further studies of the effects of CysLT2 or CysLT1/2 receptor antagonists on airway inflammation, peripheral airway functions, acute exacerbation in poor-responders to CysLT1 receptor antagonist, are required. In conclusion, we have found that inhalation of LTC4 causes CysLT2 receptor-mediated bronchoconstriction and lung air-trapping in S-hexyl GSH-treated guinea pigs. This experimental model should be useful not only for development of oral CysLT2 and CysLT1/2 receptors antagonists as therapeutic treatment for both severe asthma and asthma exacerbation, but also for understanding of the roles of CysLT2 receptors in airway pathophysiology.
Introduction Cysteinyl leukotrienes (CysLTs) LTC4, LTD4, and LTE4 are inflammatory mediators derived from arachidonic acid. They are generated in response to different immune and inflammatory stimuli [1], [2], [3], [4], and exert biological effects via two major classes of receptors: CysLT1 and CysLT2 [5]. The physiological roles of CysLT1 receptor, which are coherent with anti-bronchoconstrictive and anti-inflammatory activities of CysLT1 antagonists, such as pranlukast [6], montelukast [7] and zafirlukast [8], are well documented [9] (Fig. 1A). In contrast, the pharmacological role of CysLT2 receptor is yet less defined due to the lacking of specific antagonists. Several previously identified nonselective CysLT1/CysLT2 receptor antagonists, such as BAY u9773 [10] and DUO-LT [11], were commonly used as tools to characterize the physiological roles of CysTL2 receptor, while the poor selectivity and weak potency of these antagonists hampered further progresses. HAMI3379 (Fig. 1B) was recently reported as the potent and selective CysLT2 receptor antagonist that can effectively reverse the LTC4-induced perfusion pressure increase and contractility decrease in isolated Langendorff-perfused guinea pig hearts [12]. Thus, CysLT2 receptor may relate to cerebral spinal fluid (CSF) circulation in leukotrienes-dependent vascular reactions, thus, being a potential target for treatment of cardiovascular disease. However, there have been no reports delineating the structure–activities relationships of HAMI3379 derivatives and possible interaction modes between CysLT2 and HAMI3379. Although the X-ray crystal structure of CysLT2 has not been revealed yet, the bovine rhodopsin (bRh)-based homology modeling has been a well-established approach to study 3D structures of the GPCR receptors [13], [14]. Previously, site-directed mutagenesis has been applied to the elucidation the structures of P2Y receptors [15], [16], which showed close structural and phylogenetic relationships between P2Ys and CysLTs [17]. Recently, Parravicini et al. reported the molecular modeling of GPR17 receptor, a G-protein-coupled receptor located at intermediate phylogenetic position between two distinct receptor families: the P2Ys and CysLTs receptors [18], [19]. These methods and results provided useful guidance in the construction of 3D structure of CysLT2 receptor.