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

Abstract

The paper discusses the principal evidence that supports the concept that cell and tissue injury in infectious and post-infectious and inflammatory sequelae might involve a deleterious synergistic interaction among microbial- and host-derived pro-inflammatory agonists. Experimental models had proposed that a rapid cell and tissue injury might be induced by combinations among subtoxic amounts of three major groups of agonists generated both by microorganisms and by the host's own defense systems. These include: (1) oxidants: Superoxide, H(2)O(2), OH', oxidants generated by xanthine-xanthine-oxidase, ROO; HOC1, NO, OONO'-, (2) the membrane-injuring and perforating agents, microbial hemolysins, phospholipases A(2) and C, lysophosphatides, bactericidal cationic proteins, fatty acids, bile salts and the attack complex of complement a, certain xenobics and (3) the highly cationic proteinases, elastase and cathepsin G, as well as collagenase, plasmin, trypsin and a variety of microbial proteinases. Cell killing by combinations among the various agonists also results in the release of membrane-associated arachidonate and metabolites. Cell damage might be further enhanced by certain cytokines either acting directly on targets or through their capacity to prime phagocytes to generate excessive amounts of oxidants. The microbial cell wall components, lipoteichoic acid (LTA), lipopolysaccharides (LPS) and peptidoglycan (PPG), released following bacteriolysis, induced either by cationic proteins from neutrophils and eosinophils or by beta lactam antibiotics, are potent activators of macrophages which can release oxidants, cytolytic cytokines and NO. The microbial cell wall components can also activate the cascades of coagulation, complement and fibrinolysis. All these cascades might further synergize with microbial toxins and metabolites and with phagocyte-derived agonsits to amplify tissue damage and to induce septic shock, multiple organ failure, 'flesh-eating' syndromes, etc. The long persistence of non-biodegradable bacterial cell wall components within activated macrophages in granulomatous inflammation might be the result of the inactivation by oxidants and proteinases of bacterial autolytic wall enzymes (muramidases). The unsuccessful attempts in recent clinical trials to prevent septic shock by the administration of single antagonists is disconcerting. It does suggest however that, since tissue damage in post-infectious syndromes is most probably the end result of synergistic interactions among a multiplicity of agents, only agents which might depress bacteriolysis in vivo and 'cocktails' of appropriate antagonists, but not single antagonists, if administered at the early phases of infection especially to patients at high risk, might help to control the development of post-infectious syndromes. However, the use of adequate predictive markers for sepsis and other post-infectious complications is highly desirable. Although it is conceivable that anti-inflammatory strategies might also be counter-productive as they might...

Synergistic Aspects to Explain the Pathophysiology of Sepsis and Septic Shock-An Opinion

“…Although histone was previously suggested to be the major cause of death due to sepsis [45,46], we still argue that no single virulence factor has been clearly identified to be responsible for death in sepsis. Therefore, it is highly plausible that only multidrug strategies might be helpful and this is due to the multifactorial nature of sepsis and septic shock [22]. Furthermore, the dangers of sepsis and septic shock is also due to the rapid development of antibiotic resistance, housing and hospital crowding and in many countries to wars, poverty, ignorance and lack of adequate health care.…”

“…In numerous clinical trials of sepsis conducted, a plethora of agents have been tested as possible antidotes (see references [22] and [23] for a detailed list of publications covering this area).…”

“…Taken together, it is highly plausible that, in vivo, synergies among microbial-derived agents and agents generated by the immune responses of the host, but not only a single agonist, might explain how cells and tissues are destroyed in post-infectious sequelae [22,[27][28][29][30][31][32][33][34][35][36][37][38][39][40]. It is again enigmatic that the synergism concept of cell damage in postinflammatory sequelae is constantly disregarded.…”

Is Bacteriolysis In vivo a Friend or a Foe? Relation to Sepsis, Chronic Granulomatous Inflammation and to Oral Disorders: an Overview Hypothesis

“…The activation of neutrophils in inflamed site might also generate HOCl capable of injuring tissues. Since similarly to sepsis, periodontal disease is most probably caused by a synergistic cross-talk among a multiplicity of pro inflammatory agents, it stands to reason that multidrug strategies [16], yet to be devised, might be more efficient to suppress tissue damage than the use of single antagonists. Since survival of microbial cell-wall component in tissues may contribute to chronic inflammatory episodes, it is surprising that only a few studies have attempted to identify the possible presence of non-biodegradable microbial cell walls in the inflammatory bed either in the infected peridontium or in dental pulp (Figure 1).…”

“…A strong support for the assumption that the pathophysiology of severe infections and post-infectious sequelae may involve a "cross-talk" among a multiplicity of pro inflammatory agents, but not due to a single agonist, emerged from extensive studies conducted since the early 1970s on the pathophysiology of diseases caused by group A hemolytic streptococci [7] and later on the role of cationic peptides and of certain antibiotics as activators of bacteriolysis [8][9][10][11][12][13][14][15], which may all aggravate the outcome of post-infectious sequelae. It is therefore highly likely that multi-drug strategies, yet to be developed, might better cope with insults caused by cross-talks among a multiplicity of pro inflammatory agents [16].…”