Action of Antibodies and Plasmin on Ehrlich Ascites Tumour Cells

Ginsburg, I; Ram, Mohan

doi:10.1038/185328b0

Cited by 12 publications

(7 citation statements)

References 8 publications

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“…The present experimental model further examines the assumption that cellular injury that accompanies infectious and inflammatory processes might be due, in part, to the synergistic action among oxidants and hydrolases secreted either by activated leukocytes, released by disintegrating host cells, or elaborated by microorganisms (17,18,21). Such agents alter cell viability (14,15,17,18,21) and are also instrumental in releasing membrane-associated arachidonic acid (AA) and some of its metabolites, which might further modulate the inflammatory processes.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms by which microbial products, complement components, activated neutrophils, and macrophages injure and kill mammalian cells in infectious and inflammatory sites has been the focus of intensive investigations in the last decade (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). The idea that target cell killing by some of these agents might be the result of "multiple synergistic hits" induced by the combined action of microbial hemolysins, antibodies, complement components, and proteinases came from our earlier studies with both normal and malignant cells (14)(15)(16). We have recently also investigated the synergistic killing effects of combinations among hydrogen peroxide (H202), cationic polyelectrolytes, phospholipases A2 and C, a streptococcal hemolysin, and lipoteichoic acid on a variety of cells in culture (17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

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Killing of endothelial cells and release of arachidonic acid

et al. 1993

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51Chromium-labeled rat pulmonary artery endothelial cells (EC) cultivated in MEM medium were killed, in a synergistic manner, by mixtures of subtoxic amounts of glucose oxidase-generated H2O2 and subtoxic amounts of the following agents: the cationic substances, nuclear histone, defensins, lysozyme, poly-L-arginine, spermine, pancreatic ribonuclease, polymyxin B, chlorhexidine, cetyltrimethyl ammonium bromide, as well as by the membrane-damaging agents phospholipases A2 (PLA2) and C (PLC), lysolecithin (LL), and by streptolysin S (SLS) of group A streptococci. Cytotoxicity induced by such mixtures was further enhanced by subtoxic amounts either of trypsin or of elastase. Glucose-oxidase cationized by complexing to poly-L-histidine proved an excellent deliverer of membrane-directed H2O2 capable of enhancing EC killing by other agonists. EC treated with rabbit anti-streptococcal IgG were also killed, in a synergistic manner, by H2O2, suggesting the presence in the IgG preparation of cross-reactive antibodies. Killing of EC by the various mixtures of agonists was strongly inhibited by scavengers of hydrogen peroxide (catalase, dimethylthiourea, MnCl2), by soybean trypsin inhibitor, by polyanions, as well as by putative inhibitors of phospholipases. Strong inhibition of cell killing was also observed with tannic acid and by extracts of tea, but less so by serum. On the other hand, neither deferoxamine, HClO, TNF, nor GTP gamma S had any modulating effects on the synergistic cell killing. EC exposed either to 6-deoxyglucose, puromycin, or triflupromazin became highly susceptible to killing by mixtures of hydrogen peroxide with several of the membrane-damaging agents. While maximal synergistic EC killing was achieved by mixtures of H2O2 with either PLA2, PLC, LL, or with SLS, a very substantial release of [3H]arachidonic acid (AA), PGE2, and 6-keto-PGF occurred only if a proteinase was also added to the mixture of agonists. The release of AA from EC was markedly inhibited either by scavengers of H2O2, by proteinase inhibitors, by cationic agents, by HClO, by tannic acid, and by quinacrin. We suggest that cellular injury induced in inflammatory and infectious sites might be the result of synergistic effects among leukocyte-derived oxidants, lysosomal hydrolases, cytotoxic cationic polypeptides, proteinases, and microbial toxins, which might be present in exudates. These "cocktails" not only kill cells, but also solubilize AA and several of its metabolites. However, AA release by the various agonists can be also achieved following attack by leukocyte-derived agonists on dead cells. It is proposed that treatment by "cocktails" of adequate antagonists might be beneficial to protect against cellular injury in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Killing of endothelial cells and release of arachidonic acid

et al. 1993

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“…Our studies on the mechanisms of cell and tissue injury induced by group A streptococci (17) showed that synergy between a streptococcal hemolysin (streptolysin S, SLS) and a thiol-dependent proteinase (32); among cytotoxic antibodies, complement, and streptokinase-activated plasmin (33); and among LTA-anti-LTA antibod!Les and complement (34,35), killed mammalian ceils in vitro. These findings led us to hypothesize that, by analogy to the streptococcal models, the mechanisms of cell and tissue injury induced in inflammatory processes might perhaps also be the result of multiple synergistic interactions among leukocyte agents (oxidants, hydrolases, including phospholipases, cationic proteins, and serum factors).…”

Section: Introductionmentioning

confidence: 86%

Synergism among oxidants, proteinases, phospholipases, microbial hemolysins, cationic proteins, and cytokines

et al. 1992

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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.

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“…Historically, the synergistic phenomenon and mechanisms of cell damage induced in sepsis and most probably also in additional microbial infectious sequlae, have also been examined on tumor cells. In 1958 [23] and in 1960 [24] it was demonstrated that if the cell membranes of Ehrlich ascites tumor cells used as targets were punctured by membrane-damaging agents such as cytotoxic antibodies and complement or by streptolysin S, the cells were disintegrated by the addition of proteinases. Since then, many studies had also shown the combined/ synergistic cytotoxic effects induced by oxidants, PLA 2 , cationic peptides, such as histone, LL37, and extracts from PMNs on human umbilical cord endothelial cells, epithelial cells and also in animal models [25][26][27][28][29][30][31][32][33].…”

Section: The Synergism Paradigm and Sepsismentioning

confidence: 99%

The Pathogenesis of Sepsis: “If We Cannot beat them Alone Join Them?”

Korem¹,

Koren²,

Ginsburg³

2018

Microbiol Infect Dis

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Sepsis and septic shock are probably the least understood human disorders which worldwide take the lives of millions of patients. Sepsis may be defined as a multifactorial synergistic phenomenon where no unique damageassociated molecular patterns-alarming is identified which if successfully neutralized, might mitigate and protects against death in sepsis. Microorganisms which invade the blood stream may activate neutrophils to adhere to endothelial cells and to form oxidant-dependent nets rich in highly toxic nuclear histones claimed to be the main cause of death in sepsis due to the dysregulation of endothelial functions. However, the histone saga was recently critically debated since high levels circulating histones are also found in many clinical disorders unrelated to sepsis, therefore, histones may not be considered as a unique damage-associated molecular patterns-alarming but as additional markers of severe cell damage. We hereby argue that the main cause of tissue damage in sepsis may be an end result of a synergism between the numerous neutrophils pro inflammatory agents and the multiplicity of similar pro inflammatory agents generated by hemolytic steptoccocci and by additional pathogenic microorganism which recruit large numbers PMNs to the inflammatory sites. It is recommended that in sepsis caused by hemolytic streptococci and by additional toxigenic bacteria, a use of cocktails of antagonists might be more beneficial therapeutic strategies and this in view of the total failure to treat sepsis only by administrations of single antagonists. Also, targeting PMNs by immunological strategies should be sought for, to mitigate synergies between leukocytes and microbial cells.

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Action of Antibodies and Plasmin on Ehrlich Ascites Tumour Cells

Cited by 12 publications

References 8 publications

Killing of endothelial cells and release of arachidonic acid

Killing of endothelial cells and release of arachidonic acid

Synergism among oxidants, proteinases, phospholipases, microbial hemolysins, cationic proteins, and cytokines

The Pathogenesis of Sepsis: “If We Cannot beat them Alone Join Them?”

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