Researchers target a mouse's own cells, rather than using antibiotics,
to treat pneumonia

Date:
November 15, 2021
Source:
NIH/National Institute of Environmental Health Sciences
Summary:
Researchers have discovered a therapy that targets host cells
rather than bacterial cells in treating bacterial pneumonia in
rodents. The method involves white blood cells of the immune system
called macrophages that eat bacteria, and a group of compounds that
are naturally produced in mice and humans called epoxyeicosatrienoic
acids or EETs.



FULL STORY ========================================================================== Researchers at the National Institutes of Health have discovered
a therapy that targets host cells rather than bacterial cells in
treating bacterial pneumonia in rodents. The method involves white
blood cells of the immune system called macrophages that eat bacteria,
and a group of compounds that are naturally produced in mice and humans
called epoxyeicosatrienoic acids or EETs. The research was published in theJournal of Clinical Investigation.


========================================================================== According to the World Health Organization, pneumonia caused by
Streptococcus pneumoniae, or pneumococcal pneumonia, is the leading
cause of pneumonia deaths worldwide each year. While physicians usually prescribe antibiotics to treat this severe lung infection, treatment is
not always successful, and in some cases, the bacteria become resistant.

Matthew Edin, Ph.D., a scientist at the National Institute of
Environmental Health Sciences (NIEHS), part of NIH, wanted to find a
way to augment the body's immune system to resolve the infection.

To keep tissues healthy, EETs work to limit inflammation, but
during infections caused by S. pneumoniae and other microorganisms, inflammation ramps up after lung cells induce certain substances that
prompt macrophages to gobble up the bacteria. Edin and colleagues found
that one way to get macrophages to eat more bacteria is to decrease the
ability of EETs to do what they normally do, which is limit inflammation.

Edin led the team that found infection induces a protein called soluble
epoxide hydrolase (sEH) that degrades EETs. In contrast, when sEH is
blocked, EET levels skyrocket, hampering the macrophages' ability to
sense and eat bacteria.

As a result, the bacteria continue to reproduce in the lung, which leads
to severe lung infection and death.

At the other end of the spectrum, blocking EETs using a synthetic molecule called EEZE boosted the eating capacity of the macrophages, leading to
reduced numbers of bacteria in the lungs of mice. The scientists saw the
same result when they placed bacteria and macrophages harvested from
lung and blood samples of human volunteers in test tubes at the NIEHS
Clinical Research Unit.



========================================================================== "EEZE is safe and effective in mice, but scientists could develop
similar compounds to give to humans," said Edin, who is co-lead author
of the paper.

"These new molecules could be used in an inhaler or pill to promote
bacterial killing and make the antibiotics more effective." NIEHS
Scientific Director Darryl Zeldin, M.D., corresponding author of the
research, has spent several years studying EETs and their impact on
the human body. He and his research group determined that EETs provide beneficial cardiovascular effects, such as lowering blood pressure
and inflammation, and improving cell survival after a stroke or heart
attack. He stressed, however, that the involvement of EETs in the process
of inflammation can be good or bad depending on the context.

"EETs can suppress the inflammatory response, which is good, but if they
block it too much, they're going to make it so the macrophages can't
eat the bacteria, which is bad," said Zeldin.

Edin added that some researchers have tested sEH inhibitors -- compounds
that prevent sEH from degrading EETs -- in clinical trials to see if
they could help with pain, chronic obstructive pulmonary disease, and
high blood pressure. He cautioned that the scientists performing these
studies consider the influence of sEH inhibitors on bacterial clearance.

"They should be careful and stop using them if the individual develops pneumonia," said Edin. "Our study demonstrated that blocking sEH
means EETs may hamstring macrophages, making a lung infection worse."
Co-author Stavros Garantziotis, M.D., medical director of the NIEHS
Clinical Research Unit, was instrumental in collecting human macrophages
for the research.

"Since our study utilized lung immune cells from healthy volunteers,
we have confidence that our findings are relevant to human health,"
said Garantziotis.

========================================================================== Story Source: Materials provided by NIH/National_Institute_of_Environmental_Health_Sciences.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Hong Li, J. Alyce Bradbury, Matthew L. Edin, Joan P. Graves, Artiom
Gruzdev, Jennifer Cheng, Samantha L. Hoopes, Laura M. DeGraff,
Michael B.

Fessler, Stavros Garantziotis, Shepherd H. Schurman, Darryl
C. Zeldin.

sEH promotes macrophage phagocytosis and lung clearance of
Streptococcus pneumoniae. Journal of Clinical Investigation, 2021;
131 (22) DOI: 10.1172/JCI129679 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211115123520.htm

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