A new study provides a new therapeutic target for the treatment of sepsis

In an article published in the journal Blood, USP researchers and their collaborators propose a new strategy to prevent complications of sepsis

The proposal is to inhibit the action of a protein called gasdermin D, which the authors say can be achieved with disulfiram

The study was conducted at the Center for Research in Inflammatory Diseases (CRID), one of FAPESP-funded Research, Innovation and Dissemination Centers (RIDCs)

"We know this drug is safe because it's been used since the 1950s, and we recommend it for sepsis

Often referred to as a "systemic infection," sepsis is actually inflammation throughout the body, usually triggered by bacterial infection that enters the bloodstream

In previous research, the CRID team showed that an immune mechanism called neutrophil extracellular traps (NETs) is directly involved in tissue damage in patients with sepsis

"In our latest study, we investigated the mechanisms that allow the release of NETs, ​​in which gasdermin D is directly involved," Silva said

method

Some experiments involved white blood cells isolated from 24 sepsis patients (12 men and 12 women) who had been hospitalized 24 hours earlier

"Gasdermin D is a pore-forming protein," Silva said

Mice for in vivo experiments were submitted to a procedure to induce sepsis

"When we induced sepsis, we found that the knockout mice produced fewer NETs, ​​had less organ damage (no pulmonary edema, unlike other mice), and survived longer," Silva said

In vitro experiments confirmed that neutrophils do not release NETs even in the presence of LPS

Inhibition test

Data from the scientific literature suggest that disulfiram binds to gasdermin D to prevent the protein from forming pores in the cell membrane

They found from in vitro experiments that after treatment with disulfiram, both human and mouse neutrophils stopped releasing NETs when stimulated by LPS

In another experiment, neutrophils isolated from sepsis patients were incubated with disulfide
.
This treatment inhibited the release of NETs
.

Finally, septic-septic mice were treated with disulfiram and compared with untreated mice
.
Animals in the treated group had fewer tissue lesions (including less pulmonary edema), fewer NETs in the blood, and a better prognosis: 60 percent survived versus 20 percent in the untreated group
.
This result has intrigued the scientific community and sparked a review, also published in the journal Blood, by researcher Maxim Krimien of the University Hospital Tuebingen in Germany Maksim Klimiankou and Julia Skokowa
.

Neutrophils have multiple defenses against pathogens, including phagocytosis, production of reactive oxygen species, secretion of bactericidal enzymes, and formation of NETs
.
Neutrophils pay a high price for all these defensive actions, dying in the process of digesting, neutralizing and killing invaders
.
However, this line of defense is not perfect: it is nearly impossible to modulate the extent of neutrophil activation
.
Once activated, they often exhibit a hypersensitive phenotype, cause deleterious effects at sites of inflammation and throughout the body, and play an important role in the development and lethality of the multiple organ dysfunction process in sepsis
.
Attacking the deleterious mechanism of action of neutrophils, while preserving other functions of these cells, may be a valuable therapeutic approach during sepsis," the German researchers wrote in a comment
.

The results of this research are also the subject of a podcast produced by the Blood staff
.

next step

According to Fernando de Queiroz Cunha, a professor at FMRP-USP and principal investigator at CRID, Brazil stopped the production of dithion in 2019, which prevented the organization from conducting clinical trials
.

"It was a very cheap drug, and the company decided to take it off the market, and psychiatrists who treat alcohol-dependent patients now have to import it," Cunha said
.
"As an alternative, we are negotiating with a Brazilian pharmaceutical company.
, to develop a slightly modified molecule that could be patented and sold domestically
.
"

Cunha also revealed that CRID intends to test whether dithion can be used to prevent organ damage in COVID-19 patients
.
A previous study by the group showed that NETs are involved in the runaway inflammation triggered by SARS-CoV-2 (details: agency.
fapesp.
br/33523/)
.

article title

Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation