Monday, September 28, 2015

Sialic acid decorated multi-valent nanoparticles prevent sepsis mortality in mice

Sepsis is an uncontrolled tissue-immune [hyper]response that leads to the organ failure and frequently patients' death. At present, there is no specific treatment for sepsis, just supporting care. Obviously, sepsis represents important unmet medical condition.

New study in Science Translational Medicine provided evidence that sialic acid coated nanoparticles could prevent sepsis-induced death in mice model of acute sepsis.  

This study is based on prior evidence that binding of sialic acid (type of sugar) to its receptors called Siglecs on macrophages or neutrophils could inhibit inflammatory pathways. Here, the authors showed that unlike bi-valent anti-Siglec antibodies, administration of multi-valent sialic acid coated nanoparticles (in a form of α2,8 sacharide linkage), at both T= 0h or T= +2h, prevented endotoxin induced animal death (i.p. injection).

Similar protection was observed in anesthetized mice undergoing cecal ligation and puncture (CLP) procedure (here too, α2,8-NANO was administered i.p.).

Additionally, intra-lung administration of α2,8-NANO showed significant (but not as impressive) protection against lung inflammation (a secondary complication following cecal ligation and puncture procedure).

The authors showed that protection provided by α2,8-NANO was IL-10 dependent in endotoxin injection model (though, for some reason, the authors had used 1mg α2,8-NANO here, not 2mg α2,8-NANO, as in other figures). Also, application of exogenous IL-10 in IL-10KO mice would have provided more clear role of IL-10 here. 

Finally, the authors tried to show that α2,8-NANO application could be useful for human condition as well. They showed that α2,8-NANO could reduce inflammatory cytokine secretion from primary monocytes stimulated with endotoxin in vitro (but for some reason the authors decided to show "processed", not raw data, implying that data were either not consistent or showed too much variability).

In summary, this study suggests that sialic acid decorated multi-valent nanoparticles may play beneficial role in sepsis management (I want to note here that I am against conducting such distressing experiments on lab animals as are i.p. injection of endotoxin or CLP. We must find better alternative models).

As mention earlier, this study comes with 2 major drawbacks (that make this study not easily "translational"):

(1) while animal studies, shown here, were quite impressive, primary human cells showed less sensitivity towards α2,8-NANO application.
(2) even in animal models, α2,8-NANO was applied through i.p. injection. This route of injection is completely non-applicable for human use and I am puzzled that labs still continuing using it. Why not just use injection via i.v. route?

David Usharauli

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