Ginsburg I, Misgav R, Pinson A, Varani J, Ward P A, Kohen R
Department of Oral Biology, Hebrew University-Hadassah School of Dental Medicine, Jerusalem, Israel.
Inflammation. 1992 Oct;16(5):519-38. doi: 10.1007/BF00918977.
A striking similarity exists between the pathogenetic properties of group A streptococci and those of activated mammalian professional phagocytes (neutrophils, macrophages). Both types of cells are endowed by the ability to adhere to target cells; to elaborate oxidants, hydrolases, and membrane-active agents (hemolysins, phospholipases); and to freely invade tissues and destroy cells. From the evolutionary point of view, streptococci might justifiably be considered the forefathers of "modern" leukocytes. Our earlier findings that synergy between a streptococcal hemolysin (streptolysin S, SLS) and a streptococcal thiol-dependent proteinase and between cytotoxic antibodies+complement and streptokinase-activated plasmin readily killed tumor cells, led us to hypothesize that by analogy to the pathogenetic mechanisms of streptococci, the mechanisms of tissue destruction initiated by activated leukocytes in inflammatory sites, as well as in tissues undergoing episodes of ischemia and reperfusion, might also be the result of the synergistic effects among leukocyte-derived oxidants, phospholipases, proteinases, cytokines, and cationic proteins. The current report extends our previous synergy studies with endothelial cells to two additional cell types--monkey kidney epithelial cells and rat beating heart cells. Monolayers of 51Cr-labeled cells that had been treated by combinations of sublytic amounts of hydrogen peroxide (generated either by glucose oxidase, xanthine-xanthine oxidase, or by paraquat) and with sublytic amounts of a variety of membrane-active agents (streptolysin S, phospholipases A2 and C, lysophosphatides, histone, chlorhexidine) were killed in a synergistic manner (double synergy). Crystalline trypsin markedly enhanced cell killing by combinations of oxidant and the membrane-active agents (triple synergy). Injury to the cells was characterized by the appearance of large membrane blebs that detached from the cells and floated freely in the media, looking like lipid droplets. Cytotoxicity induced by the various combinations of agonists was depressed, to a large extent, by scavengers of hydrogen peroxide (catalase, dimethyl thiourea, and by Mn2+) but not by SOD or by deferoxamine. When cationic agents were employed together with hydrogen peroxide, polyanions (heparin, polyanethole sulfonate) were also found to inhibit cell killing. It is proposed that in order to effectively combat the deleterious toxic effects of leukocyte-derived agonists on cells and tissues, antagonistic "cocktails" comprised of cationized catalase, cationized SOD, dimethylthiourea, Mn(2+)+glycine, proteinase inhibitors, putative inhibitors of phospholipases, and polyanions might be concocted. The current literature on synergistic phenomena pertaining to mechanisms of cell and tissue injury in inflammation is selectively reviewed.
A组链球菌的致病特性与活化的哺乳动物专职吞噬细胞（中性粒细胞、巨噬细胞）的致病特性之间存在显著相似性。这两种类型的细胞都具有粘附靶细胞的能力；能够产生氧化剂、水解酶和膜活性剂（溶血素、磷脂酶）；并且能够自由侵入组织并破坏细胞。从进化的角度来看，链球菌可以被合理地认为是“现代”白细胞的祖先。我们早期的研究发现，链球菌溶血素（链球菌溶血素S，SLS）与链球菌硫醇依赖性蛋白酶之间以及细胞毒性抗体+补体与链激酶激活的纤溶酶之间的协同作用能够轻易杀死肿瘤细胞，这使我们推测，类似于链球菌的致病机制，炎症部位以及经历缺血和再灌注的组织中活化白细胞引发的组织破坏机制，也可能是白细胞衍生的氧化剂、磷脂酶、蛋白酶、细胞因子和阳离子蛋白之间协同作用的结果。本报告将我们之前对内皮细胞的协同作用研究扩展到另外两种细胞类型——猴肾上皮细胞和大鼠跳动心脏细胞。用亚溶量的过氧化氢（由葡萄糖氧化酶、黄嘌呤-黄嘌呤氧化酶或百草枯产生）与亚溶量的多种膜活性剂（链球菌溶血素S、磷脂酶A2和C、溶血磷脂、组蛋白、洗必泰）组合处理的51Cr标记细胞单层以协同方式（双重协同）被杀死。结晶胰蛋白酶显著增强了氧化剂与膜活性剂组合对细胞的杀伤作用（三重协同）。细胞损伤的特征是出现大的膜泡，这些膜泡从细胞上脱离并在培养基中自由漂浮，看起来像脂滴。过氧化氢清除剂（过氧化氢酶、二甲基硫脲和Mn2+）在很大程度上抑制了各种激动剂组合诱导的细胞毒性，但超氧化物歧化酶或去铁胺则没有。当阳离子剂与过氧化氢一起使用时，还发现聚阴离子（肝素、聚茴脑磺酸盐）会抑制细胞杀伤。有人提出，为了有效对抗白细胞衍生的激动剂对细胞和组织的有害毒性作用，可以配制由阳离子化过氧化氢酶、阳离子化超氧化物歧化酶、二甲基硫脲、Mn(2+)+甘氨酸、蛋白酶抑制剂、假定的磷脂酶抑制剂和聚阴离子组成的拮抗“鸡尾酒”。本文对目前有关炎症中细胞和组织损伤机制的协同现象的文献进行了选择性综述。
