Caughey George H
Cardiovascular Research Institute, School of Medicine, University of California at San Francisco, CA, United States; Department of Medicine, School of Medicine, University of California at San Francisco, CA, United States; Veterans Affairs Medical Center, San Francisco, CA, United States.
Eur J Pharmacol. 2016 May 5;778:44-55. doi: 10.1016/j.ejphar.2015.04.045. Epub 2015 May 7.
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 as 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 as 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.
肥大细胞富含蛋白酶，这些蛋白酶是细胞内颗粒的主要蛋白质，在细胞被激活时与组胺和肝素一起释放。这些蛋白酶中的大多数在颗粒内以及分泌到肥大细胞外时都具有活性，并且可以裂解脱颗粒肥大细胞附近和相邻组织隔室中的靶标。一些从肥大细胞释放的蛋白酶进入血液循环，可能具有深远的作用。就相对含量而言，主要的肥大细胞蛋白酶包括类胰蛋白酶、糜蛋白酶、组织蛋白酶G、羧肽酶A3、二肽基肽酶I/组织蛋白酶C以及组织蛋白酶L和S。一些肥大细胞还产生颗粒酶B、纤溶酶原激活剂和基质金属蛋白酶。类胰蛋白酶和糜蛋白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则由多种炎症细胞表达。羧肽酶A3的表达是嗜碱性粒细胞和肥大细胞共有的特性。其他蛋白酶，如肥大素，在很大程度上是嗜碱性粒细胞特异性的，尽管与小鼠嗜碱性粒细胞相比，人类嗜碱性粒细胞缺乏蛋白酶。肥大细胞蛋白酶的主要类别已成为治疗抑制剂开发的靶点。此外，一种人β-类胰蛋白酶已被提议作为一种潜在药物本身，用于使蛇毒失活。与肥大细胞蛋白酶相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、动脉粥样硬化、主动脉瘤、高血压、心肌梗死、心力衰竭、肺动脉高压以及肺和其他器官的瘢痕形成疾病。在某些情况下，在小鼠模型中进行的研究表明特定蛋白酶（或蛋白酶组）在细菌、蠕虫和其他寄生虫感染甚至过敏性炎症中具有保护或稳态作用。与此同时，人类肥大细胞亚群中表达的蛋白酶的特性和表达模式以及人类与其他哺乳动物之间的差异也更加清晰。这些考虑因素正在影响治疗性抑制特定蛋白酶靶点的优先级，以及临床前模型、疾病适应症的选择，以及抑制剂局部给药与全身给药途径的选择。
