Heat Shock Protein 72 Expressing Stress in Sepsis: Unbridgeable Gap between Animal and Human Studies—A Hypothetical “Comparative” Study

Abstract

Heat shock protein 72 (Hsp72) exhibits a protective role during times of increased risk of pathogenic challenge and/or tissue damage. The aim of the study was to ascertain Hsp72 protective effect differences between animal and human studies in sepsis using a hypothetical “comparative study” model. Forty-one in vivo (56.1%), in vitro (17.1%), or combined (26.8%) animal and 14 in vivo (2) or in vitro (12) human Hsp72 studies (P < 0.0001) were enrolled in the analysis. Of the 14 human studies, 50% showed a protective Hsp72 effect compared to 95.8% protection shown in septic animal studies (P < 0.0001). Only human studies reported Hsp72-associated mortality (21.4%) or infection (7.1%) or reported results (14.3%) to be nonprotective (P < 0.001). In animal models, any Hsp72 induction method tried increased intracellular Hsp72 (100%), compared to 57.1% of human studies (P < 0.02), reduced proinflammatory cytokines (28/29), and enhanced survival (18/18). Animal studies show a clear Hsp72 protective effect in sepsis. Human studies are inconclusive, showing either protection or a possible relation to mortality and infections. This might be due to the fact that using evermore purified target cell populations in animal models, a lot of clinical information regarding the net response that occurs in sepsis is missing.

The effect of 2 mMol glutamine supplementation on HSP70 and TNF-α release by LPS stimulated blood from healthy children

“…HSP70 forms part of the cellular response to stress [1]. Levels of extracellular HSP70 are increased, in response to infection, forming a network of molecules discharged by stressed or damaged cells [2,3].…”

“…cell culture, animal, human). A recent analysis considering the effect of HSP70 in animal models compared to humans indicate that whilst HSP70 confers an almost entirely protective effect in animals (97.1%) the same may not be true in humans, with only a 50% protective effect demonstrated [1]. Therefore the clinical benefit of HSP70 upregulation during times of stress remains unclear, especially as both low and high levels in children and adults are associated with increased risk in children and adults mortality and infection risk [1,18].…”

“…A recent analysis considering the effect of HSP70 in animal models compared to humans indicate that whilst HSP70 confers an almost entirely protective effect in animals (97.1%) the same may not be true in humans, with only a 50% protective effect demonstrated [1]. Therefore the clinical benefit of HSP70 upregulation during times of stress remains unclear, especially as both low and high levels in children and adults are associated with increased risk in children and adults mortality and infection risk [1,18]. In adults following trauma HSP70 levels 15 ng/ml is associated with increased mortality [19], conversely, levels !60 ng/ml is associated with increased mortality in traumatic brain injury [20] and severe sepsis in adults [21] and children [22].…”

Polymyxin B hemoperfusion in septic shock: nothing overmuch (Meden Agan)!

“…Last decades the concept of targeted interventions to decrease the circulating mediators of sepsis to intercept the dysregulated host response grew enthusiasm, and endotoxin was a reliable target to consider for therapy. Treatment interventions at various steps of the endotoxin pathway, including the heat shock protein-72 and -90 "danger signal" induction (3), have been tested experimentally in human in vivo and in vitro studies (4,5) without convincing results (6,7). Attempts to remove endotoxin with monoclonal antibodies failed, so extracorporeal removal by hemoperfusion was introduced using polymyxin B cartridges, where endotoxin can be bound and neutralized (8).…”

Prognostic markers of pediatric meningococcal sepsis

“…Outside cells, Hsp72 induces the activation of macrophages, monocytes, dendritic cells and natural killer cells. Accordingly, extracellular Hsps act as a 'danger signal,' further activating immune competent cells through lipoprotein TLR4/ CD14-dependent signaling [8]. Unfortunately, immunity-related genes are subject to epigenetic regulation, potentially rendering the host immune-deficient for a long period after the initial sepsis challenge [9].…”