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  • In conclusion we developed a

    2020-10-17

    In conclusion, we developed a new CysLT1 and CysLT2 receptors-mediated anaphylaxis guinea pig model that can be useful for screening both CysLT2 receptor and CysLT1/2 receptor antagonists. In addition, we have shown that the dual CysLT1/2 receptor antagonist ONO-6950 can exert protective effect against anaphylactic response or asthma exacerbation. To further clarify the role of CysLT2 receptors in asthma, experiments using this novel model or clinical studies with CysLT2 receptors or CysLT1/2 dual antagonists are required.
    Introduction The cysteinyl-leukotrienes (cysLTs), LTC4, LTD4, and LTE4, are pro-inflammatory lipid mediators, involved in many pathologies including allergic asthma and rhinitis. They are derived from arachidonic selonsertib and synthesized through the 5-lipoxygenase pathway in different cell types, including leukocytes (mast cells, basophils, eosinophils and macrophages…), platelets and endothelial cells [1]. CysLTs bind to at least three G-protein-coupled receptors (GPCRs). CysLT1 and CysLT2, share 38% homology in structure. CysLT1 receptor binds preferentially LTD4 (LTD4>LTC4≫LTE4), whereas the CysLT2 receptor has no preference between LTD4 and LTC4 (LTC4=LTD4≫LTE4) [2], [3]. A third receptor, GPR99, has been recently characterized and shown to be an LTE4 receptor, with less affinity for the other two cysLTs (LTE4≫LTD4>LTC4) [4]. The CysLT1 receptor is mostly expressed in human lung, on smooth muscle cells and macrophages, but also on peripheral blood cells, such as eosinophils, basophils, monocytes and B and T lymphocytes [5], [6], [7]. On the other hand, the CysLT2 receptor is more ubiquitous and is found on interstitial lung macrophages and on circulating eosinophils and monocytes [8]. These two receptors are also expressed in other organs, like on the spleen, intestines, pancreas and prostate for CysLT1 receptor, and in the heart, brain, adrenal gland, placenta and spleen for CysLT2 receptor [9], [10], [11]. The CysLT1 receptor is highly expressed in the lung, which may be relevant for its implication in pulmonary diseases like asthma. In fact, specific antagonists of the CysLT1 receptor (pranlukast, montelukast and zafirlukast) are used in the clinic to control bronchoconstriction and inflammation in asthma and allergic rhinitis [12]. In the midst of an inflammatory environment, CysLT1 receptor expression is up-regulated by many cytokines, including the Th2 cytokines IL-4 and IL-13 in monocytes and macrophages, IL-5 in eosinophils, IL-1β in HUVEC, TGFβ, IFN-γ and IL-13 in pulmonary smooth muscle cells [7], [13], [14], [15], [16], [17], [18], [19]. As a GPCR, the CysLT1 receptor is coupled to the G-proteins Gαi and Gαq [20], [21]. Through different pathways, including MAPKinases and NF-κB, it induces the transcription of several genes implicated in inflammation, such as IL-8, MCP-1, IL-4, TGFβ, P-selectin, CXC chemokine ligand 2 and NO synthase [22], [23], [24], [25], [26], [27]. Polymorphisms in the CysLT1 receptor have been identified which are associated with atopy, an important risk factor for asthma. In the English and Spanish populations, the variant T927C, due to a synonymous mutation in the CysLT1 receptor gene was associated to atopy [28]. Atopy is a genetic predisposition to develop allergies, characterized by an elevation of IgE, and is often associated with the production of inflammatory mediators such as cysLTs [29]. In addition, a serine substitution in the amino acid structure of the CysLT1 receptor resulted in the variants CysLT1-G300S and CysLT1-I206S, the only identified variants of CysLT1 due to exonic mis-sense mutations. Those have been discovered and studied in the genetically isolated population of Tristan Da Cunha, which has a high prevalence of atopy and asthma. The receptor variant CysLT1-G300S has been significantly associated with atopy whereas the polymorphism CysLT1-I206S was not associated with atopy, in this population [30], [31].