Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, P.O. Box 2034, Pretoria 0001, South Africa ; Tshwane Academic Division of the National Health Laboratory Service, Pretoria 0001, South Africa.
Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria, P.O. Box 2034, Pretoria 0001, South Africa.
J Immunol Res. 2014;2014:608930. doi: 10.1155/2014/608930. Epub 2014 May 25.
Cysteinyl leukotrienes (cysLTs) are produced predominantly by cells of the innate immune system, especially basophils, eosinophils, mast cells, and monocytes/macrophages. Notwithstanding potent bronchoconstrictor activity, cysLTs are also proinflammatory consequent to their autocrine and paracrine interactions with G-protein-coupled receptors expressed not only on the aforementioned cell types, but also on Th2 lymphocytes, as well as structural cells, and to a lesser extent neutrophils and CD8(+) cells. Recognition of the involvement of cysLTs in the immunopathogenesis of various types of acute and chronic inflammatory disorders, especially bronchial asthma, prompted the development of selective cysLT receptor-1 (cysLTR1) antagonists, specifically montelukast, pranlukast, and zafirlukast. More recently these agents have also been reported to possess secondary anti-inflammatory activities, distinct from cysLTR1 antagonism, which appear to be particularly effective in targeting neutrophils and monocytes/macrophages. Underlying mechanisms include interference with cyclic nucleotide phosphodiesterases, 5'-lipoxygenase, and the proinflammatory transcription factor, nuclear factor kappa B. These and other secondary anti-inflammatory mechanisms of the commonly used cysLTR1 antagonists are the major focus of the current review, which also includes a comparison of the anti-inflammatory effects of montelukast, pranlukast, and zafirlukast on human neutrophils in vitro, as well as an overview of both the current clinical applications of these agents and potential future applications based on preclinical and early clinical studies.
半胱氨酰白三烯（cysLTs）主要由先天免疫系统的细胞产生，特别是嗜碱性粒细胞、嗜酸性粒细胞、肥大细胞和单核细胞/巨噬细胞。尽管具有强大的支气管收缩活性，但 cysLTs 也具有促炎作用，这是由于它们与 G 蛋白偶联受体的自分泌和旁分泌相互作用所致，这些受体不仅表达在上述细胞类型上，还表达在 Th2 淋巴细胞以及结构细胞上，并且在一定程度上还表达在中性粒细胞和 CD8(+)细胞上。认识到 cysLTs 参与各种类型的急性和慢性炎症性疾病的免疫发病机制，特别是支气管哮喘，促使开发了选择性 cysLT 受体-1（cysLTR1）拮抗剂，特别是孟鲁司特、普仑司特和扎鲁司特。最近，这些药物也被报道具有不同于 cysLTR1 拮抗作用的二级抗炎活性，这些活性似乎特别有效地针对中性粒细胞和单核细胞/巨噬细胞。潜在的机制包括干扰环核苷酸磷酸二酯酶、5'-脂氧合酶和促炎转录因子核因子 kappa B。本综述的主要重点是常用的 cysLTR1 拮抗剂的这些和其他二级抗炎机制，其中还包括比较孟鲁司特、普仑司特和扎鲁司特对体外人中性粒细胞的抗炎作用，以及这些药物的当前临床应用概述以及基于临床前和早期临床研究的潜在未来应用。
