Blockade of Exosome Generation with GW4869 Dampens the Sepsis-Induced Inflammation and Cardiac Dysfunction

[junkcrap50]

Emphasis mine.

Blockade of Exosome Generation with GW4869 Dampens the Sepsis-Induced Inflammation and Cardiac Dysfunction
Kobina Essandoh,1,* Liwang Yang,1,6,* Xiaohong Wang,1 Wei Huang,2 Dongze Qin,1,7 Jiukuan Hao,3 Yigang Wang,2 Basilia Zingarelli,4 Tianqing Peng,5 and Guo-Chang Fan1,*
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The publisher's final edited version of this article is available at Biochim Biophys Acta

Abstract
Sepsis is an infection-induced severe inflammatory disorder that leads to multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory cytokines are culprit for triggering cardiac dysfunction in sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with GW4869, an inhibitor of exosome biogenesis/release, followed by endotoxin (LPS) challenge. In vivo, we injected wild-type (WT) mice with GW4869 for 1 h prior to endotoxin treatment or cecal ligation/puncture (CLP) surgery. We observed that pre-treatment with GW4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12 h after LPS treatment or CLP surgery, WT mice pretreated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in sepsis dampens the sepsis-triggered inflammatory response and thereby, improves cardiac function and survival.

Keywords: sepsis, exosomes, cardiac dysfunction, macrophages, inflammatory response

 

[junkcrap50]

bacteria-infected macrophages are pro-inflammatory.

perhaps there might be viral-infected macrophages doing the same thing.

 

[junkcrap50]

From the introduction of the paper:

Currently, GW4869, a neutral sphingomyelinase inhibitor, is the most widely used pharmacological agent for blocking exosome generation [29–32]. GW4869 inhibits the ceramide-mediated inward budding of multivesicular bodies (MVBs) and release of mature exosomes from MVBs [30].

Seems like sphingomyelin is important in exosome release.

 

[Wonko]

Surely this could only ever be a holding action?

My, limited, understanding is that these things will keep being produced, that the only thing that stops that normally is death.

So all blocking them can achieve is buy time, sometimes that time might allow things to resolve but surely a lot of the time it's just prolonging things?

A bit like trying to stem someone bleeding out with a transfusion, unless the dirty great hole is fixed all you're doing is delaying things.

And in most cases they don't seem to have a clue what a metaphorical 'hole' is let alone how to fix it.

 

[Hoopoe]

From the introduction of the paper:

Seems like sphingomyelin is important in exosome release.

Unfortunately the data on sphingomyelin in ME/CFS is currently contradictory. One study found low levels, another high levels. This could be due to the technology still being unreliable or some other problem. So we don't know how sphingomyelin moves in this illness, or if it's even much different.

 

[junkcrap50]

Surely this could only ever be a holding action?
....
And in most cases they don't seem to have a clue what a metaphorical 'hole' is let alone how to fix it.

I'm not suggesting this will be a fix for ME/CFS disease. Maybe it could be. Perhaps it could "hold" long enough so that, if you believe in Ron Davis's or Nancy Klima's theory, our body can "reset" itself and get us out of some metabolic trap. Who knows.

Initially the paper looked interesting because it showed an exosome-driven mechanism of sepsis (which according to several researcher accounts ME/CFS resembles) and can control severity of sepsis. So it could possibly provide an explanation for ME/CFS.

But this research may also help in Ron Davis's testing of the nanochip. If this drug GW4869 blocks the "something in the blood" and can turn ME/CFS serum into "normal looking/working" serum on the different cells they test, then it would lend credence to the exosome theory. It would just be 1 more drug for them to test on the chip.