Time to look for therapeutic targets in sepsis

Time to look for therapeutic targets in sepsis
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Sepsis is a medical condition that few patients have heard of and most doctors dread – But could scientists bring about new therapeutic targets for sufferers?

For those with sepsis, the body’s response to attack by bacteria can trigger a cascade of cellular self-destruction that inadvertently causes blood clots, multi-organ failure, and death. The immune system functions as a sort of cellular Pac-Man, using white blood cells to hunt out the “bad guys,” initiating attacks and counter-attacks. However, in extreme cases, white blood cells trigger their own death in an attempt to destroy the infection. Sometimes it works, but when it doesn’t, the complications are dangerous.

The world of sepsis

Therapeutic targets to treat severe cases of sepsis is miserably small, and physicians have little to provide other than antibiotics, fluids, and hope.

Exciting new research has defined the chain of molecular events that goes awry in sepsis, opening up opportunities for new treatments to fight the condition that affects more than a million Americans each year and kills up to a third of them.

Two collaborating laboratories at the University of Kentucky, USA, were able to establish the events within white blood cells that progresses from inflammation activation to a type of programmed cell death called pyroptosis — and culminates in the damaging blood clots.

“Recent studies have uncovered the mechanism of pyroptosis following inflammasome activation, but we didn’t know how pyroptotic cell death drives the disease process,” said Zhenyu Li, an associate professor in the University of Kentucky’s Department of Molecular and Cellular Biochemistry.

“If we could uncover that link, it would open up possibilities for therapies that target inflammatory, infection-mediated clotting.”

An important link between inflammation and blood clotting

The teams, led by Li and Yinan Wei, Ph.D. of UK’s Department of Chemistry, determined that certain bacterial proteins and endotoxin trigger inflammasome activation in white blood cells, causing pyroptosis. During pyroptosis, pores form in the white blood cell membrane that result in the release of tissue factor, a protein known to initiate the clotting process.

“Our data establish inflammasome activation as an important link between inflammation and blood clotting,” Li said.

“Our findings advance the understanding of the relationship between bacterial infections and coagulation as well as provide evidence that inflammasome may be a potential therapeutic target for sepsis.”

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