Mast cell proteases as pharmacological targets.
Mast cell proteases as pharmacological targets.
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DOI：
10.1016/j.ejphar.2015.04.045
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发表时间：
2016-05-05
影响因子：
5
通讯作者：
Caughey GH
中科院分区：
文献类型：
--
作者：
Caughey GH
肥大细胞富含蛋白水解酶，是细胞内颗粒的主要蛋白质，被激活的细胞释放组胺和肝素。这些酶中的大多数在分泌时在颗粒内以及肥大细胞外都是活跃的，并能在脱颗粒的肥大细胞附近和相邻的组织间隔中切割靶点。肥大细胞释放的一些蛋白水解酶进入血液，可能具有深远的作用。就相对数量而言，肥大细胞酶主要包括类胰蛋白酶、糜酶、组织蛋白酶G、羧肽酶A3、二肽基肽酶I/组织蛋白酶C、组织蛋白酶L和组织蛋白酶S。一些肥大细胞还产生颗粒酶B、纤溶酶原激活物和基质金属蛋白酶。类胰蛋白酶和糜酶几乎完全是肥大细胞特异性的，而其他蛋白酶，如组织蛋白酶G、C和L，则由各种炎症细胞表达。羧肽酶A3的表达是嗜碱性粒细胞和肥大细胞共有的特性。其他的蛋白水解酶，如Mastins，在很大程度上是嗜碱性粒细胞所特有的，尽管与小鼠的同类相比，人类嗜碱性粒细胞缺乏蛋白水解酶。肥大细胞蛋白水解酶的主要类别已成为治疗抑制剂开发的靶点。此外，一种人的β-类胰蛋白酶被提议作为一种潜在的药物本身，用来灭活蛇毒。与肥大细胞蛋白水解酶有关的疾病包括过敏性疾病，如哮喘、湿疹和过敏反应，但也包括非过敏性疾病，如炎症性肠病、自身免疫性关节炎、动脉硬化、主动脉瘤、高血压、心肌梗死、心力衰竭、肺高压和肺部和其他器官的疤痕疾病。在某些情况下，在小鼠模型上进行的研究表明，在细菌、蠕虫和其他寄生虫的感染中，甚至在过敏性炎症中，特定的蛋白水解酶(或一组蛋白水解酶)具有保护或内环境稳定的作用。与此同时，人类肥大细胞亚群和人类与其他哺乳动物表达的蛋白水解酶的性质和表达模式的差异也出现了更清晰的图景。这些考虑因素正在影响特定蛋白水解酶靶点治疗抑制的优先顺序，以及临床前模型、疾病适应症的选择，以及局部和全身给药途径的选择。
Mast cells are rich in proteases, which are the major proteins of intracellular granules and are released with histamine and heparin by activated cells. Most of these proteases are active in the granule as well outside of the mast cell when secreted, and can cleave targets near degranulating mast cells and in adjoining tissue compartments. Some proteases released from mast cells reach the bloodstream and may have far-reaching actions. In terms of relative amounts, the major mast cell proteases include the tryptases, chymases, cathepsin G, carboxypeptidase A3, dipeptidylpeptidase I/cathepsin C, and cathepsins L and S. Some mast cells also produce granzyme B, plasminogen activators, and matrix metalloproteinases. Tryptases and chymases are almost entirely mast cell-specific, whereas other proteases, such as cathepsins G, C, and L are expressed by a variety of inflammatory cells. Carboxypeptidase A3 expression is a property shared by basophils and mast cells. Other proteases, such as mastins, are largely basophil-specific, although human basophils are protease-deficient compared with their murine counterparts. The major classes of mast cell proteases have been targeted for development of therapeutic inhibitors. Also, a human β-tryptase has been proposed as a potential drug itself, to inactivate of snake venins. Diseases linked to mast cell proteases include allergic diseases, such as asthma, eczema, and anaphylaxis, but also include non-allergic diseases such inflammatory bowel disease, autoimmune arthritis, atherosclerosis, aortic aneurysms, hypertension, myocardial infarction, heart failure, pulmonary hypertension and scarring diseases of lungs and other organs. In some cases, studies performed in mouse models suggest protective or homeostatic roles for specific proteases (or groups of proteases) in infections by bacteria, worms and other parasites, and even in allergic inflammation. At the same time, a clearer picture has emerged of differences in the properties and patterns of expression of proteases expressed in human mast cell subsets, and in humans versus other mammals. These considerations are influencing prioritization of specific protease targets for therapeutic inhibition, as well as options of pre-clinical models, disease indications, and choice of topical versus systemic routes of inhibitor administration.