In this study, we checked whether HSP70 preparations of different origins are able to protect model animals (rats) from endotoxic shock and modify the response of myeloid cells to lipopolysaccharide (LPS) challenge. It was shown that HSP70 preparations can effectively protect organisms from endotoxic shock by strongly decreasing mortality and restoring both homeostasis and various hemodynamic characteristics. At the cellular level, HSP70 preparations significantly inhibit LPS-induced reactive oxygen species production in various myeloid cells and decrease NO expression in macrophages, which is enhanced after LPS priming. In parallel, HSP70 preconditioning partially normalizes neutrophil apoptosis, which is disturbed as a result of LPS stimulation. These results suggest that the antiseptic actions of HSP70 preparations are probably realized at the level of receptor membrane complexes of myeloid cells, which represent the major target of LPS action. Taken together, our findings show that extracellular mammalian HSP70 may play an important role in innate immunity modulation and stimulation of endogenous protective mechanisms, both at the cellular and organism levels, which make this protein a promising base for the development of efficient antiseptic drugs.
It has been previously reported that pretreatment with exogenous heat shock protein 70 (Hsp70) is able to protect cells and animals from the deleterious effects of bacterial lipopolysaccharide (LPS) produced by Gramnegative bacteria. However, the effects of Hsp70 pretreatment on lipoteichoic acid (LTA) challenge resulted from Gram-positive bacteria infection have not been fully elucidated. In this study, we demonstrated that preconditioning with human recombinant Hsp70 ameliorates various manifestations of systematic inflammation, including reactive oxygen species, TNFα, and CD11b/CD18 adhesion receptor expression induction observed in different myeloid cells after LTA addition. Therefore, exogenous Hsp70 may provide a mechanism for controlling excessive inflammatory responses after macrophage activation. Furthermore, in a rat model of LTA-induced sepsis, we demonstrated that prophylactic administration of exogenous human Hsp70 significantly exacerbated numerous homeostatic and hemodynamic disturbances induced by LTA challenge and partially normalized the coagulation system and multiple biochemical blood parameters, including albumin and bilirubin concentrations, which were severely disturbed after LTA injections. Importantly, prophylactic intravenous injection of Hsp70 before LTA challenge significantly reduced mortality rates. Thus, exogenous mammalian Hsp70 may serve as a powerful cellular defense agent against the deleterious effects of bacterial pathogens, such as LTA and LPS. Taken together, our findings reveal novel functions of this protein and establish exogenous Hsp70 as a promising pharmacological agent for the prophylactic treatment of various types of sepsis.
The protective effects of 70-kDa heat shock proteins (HSP70) were studied following the intravenous administration in rats with endotoxic shock. The antitoxic effects of both bovine HSP70 (bHSP70) and human recombinant HSP70 (hrHSP70) were compared. The preventive uptake of HSP70 decreased the toxic influence of the E. coll endotoxin on the rats' bodies and significantly increased the survival of the animals during the experiment.
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