Gamma globulin, Evan's blue, aprotinin A PLA2 inhibitor, tetracycline and antioxidants protect epithelial cells against damage induced by synergism among streptococcal hemolysins, oxidants and proteinases: relation to the prevention of post-streptococcal sequelae and septic shock.
An in vitro model was employed to study the potential role of streptococcal extra-cellular products, rich in streptolysin O, in cellular injury as related to streptococcal infections and post-streptococcal sequelae. Extra-cellular products (EXPA) rich in streptolysin O were isolated from type 4, group A hemolytic streptococci grown in a chemostat, in a synthetic medium. EXPA induced moderate cytopathogenic changes in monkey kidney epithelial cells and in rat heart cells pre-labeled with 3H-arachidonate. However very strong toxic effects were induced when EXP was combined with oxidants (glucose oxides generated H2O2, AAPH-induced peroxyl radical (ROO.), NO generated by sodium nitroprusside) and proteinases (plasmin, trypsin). Cell killing was distinctly synergistic in nature. Cell damage induced by the multi-component cocktails was strongly inhibited either by micromolar amounts of gamma globulin, and Evan's blue which neutralized SLO activity, by tetracycline, trasylol (aprotinin), epsilon amino caproic acid and by soybean trypsin inhibitor, all proteinase inhibitors as well as by a non-penetrating PLA2 inhibitor A. The results suggest that fasciitis, myositis and sepsis resulting from infections with hemolytic streptococci might be caused by a coordinated 'cross-talk' among microbial, leukocyte and additional host-derived pro-inflammatory agents. Since attempts to prolong lives of septic patients by the exclusive administration of single antagonists invariably failed, it is proposed that the administration of 'cocktails' of putative inhibitors against major pro-inflammatory agonizes generated in inflammation and infection might protect against the deleterious effects caused by the biochemical and pharmacological cascades which are known to be activated in sepsis.
Ginsburg
I
I
Department of Oral Biology, Hebrew University-Hadassah, School of Dental Medicine, Jerusalem, Israel. ginsburg@cc.huji.ac.il
Sadovnic
M
M
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D007611:Aprotinin / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D010450:Endopeptidases / Q000378:metabolism / Q000633:toxicity*; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects; D004912:Erythrocytes / Q000502:physiology; D005070:Evans Blue / Q000494:pharmacology; D000882:Haplorhini; D006461:Hemolysis; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology; D016877:Oxidants / Q000633:toxicity*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D051381:Rats; D012772:Shock, Septic / Q000382:microbiology / Q000517:prevention & control*; D013290:Streptococcal Infections / Q000150:complications / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000472:pathogenicity*; D013301:Streptolysins / Q000633:toxicity*; D013752:Tetracycline / Q000494:pharmacology; D005719:gamma-Globulins / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000975:Antioxidants; D016877:Oxidants; D013301:Streptolysins; D005719:gamma-Globulins; D016718:Arachidonic Acid; D005070:Evans Blue; D007611:Aprotinin; D006861:Hydrogen Peroxide; D010741:Phospholipases A; D054467:Phospholipases A2; D010450:Endopeptidases; D013752:Tetracycline