Gamma globulin, Evan's blue, aprotinin A PLA₂inhibitor, 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

Abstract

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.

Multi-drug strategies are necessary to inhibit the synergistic mechanism causing tissue damage and organ failure in post infectious sequelae

“…It is also of great interest that the cytolytic effects induced by combinations among perforators, oxidants and proteinases can be markedly depressed either by inhibiting the perforator or of the oxidant suggesting that the simultaneous presence of these two agents is absolutely required to induce an irreversible membrane injury (Ginsburg and Sadovnic, 1998). These studies implicate that paradoxically, perhaps, during microbial infections there might occur a deleterious synergistic interaction among microbial and host-derived agonists.…”

“…The concept that tissue damage initiated during and following microbial invasion, might be caused by interaction between several pro-inflammatory agonists, had emerged form observations on the pathophysiology of tissue damage induced by catalase-negative bacteria (streptococci, clostridiae) (Ginsburg, 1972(Ginsburg, , 1996(Ginsburg, , 1998Ginsburg et al, 1995Ginsburg et al, , 1998Ginsburg and Sadovnic, 1998). Already by 1959, it had been shown that tumour cells injured by the membrane-perforating toxin, steptolysin S (SLS), were rapidly disintegrated by non-cytolytic amounts of a cysteine proteinase derived from streptococci (Ginsburg, 1972).…”

“…It has also been questioned recently whether the continuation of clinical trials with only a marginal benefit, is ethical (Nasraway, 1999). This pessimistic stand might stem from the realization that no single omnipotent pro-inflammatory agonist exists, which if effectively administered might avert the complex synergistic interactions among a multiplicity of agonists responsible for the initiation of cell and tissue injury (Ginsburg and Kohen, 1995;Ginsburg, 1998;Ginsburg and Sadovnic, 1998;Baue, 1998;Wheeler and Bernard, 1996).…”