Old drug may have new trick: Protecting against COVID-19 lung injury,
study finds

Date:
February 8, 2022
Source:
Weill Cornell Medicine
Summary:
An FDA-approved drug that has been in clinical use for more than 70
years may protect against lung injury and the risk of blood clots
in severe COVID-19 and other disorders that cause immune-mediated
damage to the lungs, according to a preclinical study.



FULL STORY ==========================================================================
An FDA-approved drug that has been in clinical use for more than 70
years may protect against lung injury and the risk of blood clots in
severe COVID-19 and other disorders that cause immune-mediated damage
to the lungs, according to a preclinical study from researchers at Weill Cornell Medicine and Cold Spring Harbor Laboratory.


==========================================================================
The researchers, whose report appears Feb. 8 in JCI Insight, found that
the drug disulfiram protected rodents from immune-mediated lung injury in
two separate models of this type of injury: infection with the SARS-CoV-
2 coronavirus that causes COVID-19, and a lung failure syndrome called
TRALI that in rare cases occurs after blood transfusion.

"As we learn more about the underlying biology of these lung injuries,
we may be able to specifically target the processes that are damaging
the lung tissue," said senior co-author Dr. Robert Schwartz, an associate professor of medicine in the Division of Gastroenterology and Hepatology
at Weill Cornell Medicine and a hepatologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Both types of lung injury are now known to be driven in part by immune
cells' formation of web-like structures called neutrophil extracellular
traps, or NETs. These can trap and kill infectious organisms, but can also
be harmful to lung tissue and blood vessels, causing the accumulation
of fluid in the lungs (edema) and promoting the development of blood
clots. Disulfiram blocks one of the steps in NETs formation.

The study was a collaboration between Dr. Schwartz's research group and
a group led by Dr. Mikala Egeblad, professor and cancer center co-leader
at Cold Spring Harbor Laboratory.

Serendipity has attached to disulfiram almost from the start of
its history as a medicine. The compound was originally used in the
production of rubber, and was later investigated as an anti-parasite
treatment. Incidental observations that people taking it became mildly
sick whenever they drank alcohol led to its FDA approval in 1951 as a
deterrent to alcohol consumption for people with alcohol use disorder.



========================================================================== Scientists found in 2020 that disulfiram also inhibits part of the
inflammatory process that can lead to NET formation by white blood cells
called neutrophils.

The finding prompted the testing of disulfiram as a NET blocker. "NETs
will damage the tissue, but since disulfiram interferes with gasdermin D,
a molecule needed to produce NETs, no NETs are formed after disulfiram treatment," Dr.

Egeblad said.

After confirming in lab-dish experiments that disulfiram does greatly
reduce the formation of NETs by human and mouse neutrophils, the
researchers tested it in models of TRALI and COVID-19, two diseases
that are known to feature extensive neutrophil invasion of the lungs,
NET formation and often fatal lung damage.

In a mouse model of TRALI, disulfiram treatment a day before and then
again three hours before induction of the syndrome allowed 95 percent of
the animals to survive, compared to just 40 percent of those not treated
with the drug. The findings showed that disulfiram, apparently by reducing
NET formation, blocked the progressive damage to lung tissue and vessels
that occurred in untreated mice, and in so doing allowed lung function
to stabilize and recover relatively quickly after initial damage. By
contrast, an inhaled drug called DNase 1, which has been investigated as
a potential TRALI treatment, had no significant effect in improving the
mouse survival rate even when administered minutes before TRALI induction.

In earlier collaborative work published in the Journal of Experimental Medicine, autopsy results suggested that NETs were present in severe
COVID-19 patients and raised a novel possibility.

"Currently there aren't any good treatment options for COVID-related
lung injury, so disulfiram appears to be worth investigating further in
this regard, particularly in severe COVID-19 patients," Dr. Schwartz said.

Next the researchers tested disulfiram in a golden hamster model of
COVID-19.

This form of COVID-19 is less severe than what is seen in the worst human cases, but disulfiram treatment a day before or a day after infection with SARS-CoV-2 led to clearly favorable outcomes: less NET formation, less
scar- like tissue formation (fibrosis) in the lungs, and gene activity
changes suggesting a significant reduction in the harmful inflammatory
response without impairment of antiviral immunity.

By comparison, the standard severe-COVID-19 treatment dexamethasone,
an immune- suppressing steroid drug, did less to protect lung tissue
from disease-related changes, and led to higher levels of SARS-CoV-2 in
the lungs.

"Disulfiram's strong inhibitory effect on NET formation and its
improvement of disease outcomes in different rodent models highlight
the potential for its use and for the future development of even better inhibitors of NET formation in a variety of diseases," Dr. Schwartz
said. Other researchers have begun small clinical trials of disulfiram
in COVID-19 patients, although the results of those trials have not yet
been published, he noted.

========================================================================== Story Source: Materials provided by Weill_Cornell_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal References:
1. Jose M. Adrover, Lucia Carrau, Juliane Dassler-Plenker, Yaron Bram,
Vasuretha Chandar, Sean Houghton, David Redmond, Joseph R. Merrill,
Margaret Shevik, Benjamin R. tenOever, Scott K. Lyons, Robert E.

Schwartz, Mikala Egeblad. Disulfiram inhibits neutrophil
extracellular trap formation protecting rodents from acute
lung injury and SARS-CoV- 2 infection. JCI Insight, 2022; DOI:
10.1172/jci.insight.157342
2. Betsy J. Barnes, Jose M. Adrover, Amelia Baxter-Stoltzfus,
Alain Borczuk,
Jonathan Cools-Lartigue, James M. Crawford, Juliane Dassler-Plenker,
Philippe Guerci, Caroline Huynh, Jason S. Knight, Massimo Loda,
Mark R.

Looney, Florencia McAllister, Roni Rayes, Stephane Renaud,
Simon Rousseau, Steven Salvatore, Robert E. Schwartz, Jonathan
D. Spicer, Christian C. Yost, Andrew Weber, Yu Zuo, Mikala
Egeblad. Targeting potential drivers of COVID-19: Neutrophil
extracellular traps. Journal of Experimental Medicine, 2020; 217
(6) DOI: 10.1084/jem.20200652 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220208143320.htm

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