November 28, 2021

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

Press release

Monday, November 15, 2021

NIH scientists say this approach could be a new way to treat pneumonia in humans.

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

According to the World Health Organization, pneumonia caused by Streptococcus pneumoniae, or pneumococcal pneumonia, is the leading cause of death from pneumonia worldwide each year. Although doctors usually prescribe antibiotics to treat this serious lung infection, treatment is not always effective and in some cases the bacteria become resistant.

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

To keep tissue healthy, TEEs work to limit inflammation, but in infections caused by S. pneumoniae and other microorganisms, inflammation intensifies after lung cells induce certain substances that cause macrophages to engulf bacteria. Edin and his colleagues have found that one way to get macrophages to eat more bacteria is to decrease the ability of TEEs to do what they normally do, which is to limit inflammation.

Edin led the team that discovered that the infection induces a protein called soluble epoxide hydrolase (sEH) that degrades EETs. In contrast, when sEH is blocked, EET levels skyrocket, hampering the ability of macrophages to detect and eat bacteria. As a result, the bacteria continue to reproduce in the lungs, resulting in severe lung infection and death.

On the other end of the spectrum, blocking EETs using a synthetic molecule called EEZE increased the feeding capacity of macrophages, leading to a reduction in the number of bacteria in the lungs of mice. Scientists saw the same result when they placed bacteria and macrophages harvested from lung and blood samples of human volunteers into 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, co-lead author of the article. “These new molecules could be used in an inhaler or a pill to help kill bacteria and make antibiotics more effective.”

NIEHS Scientific Director Darryl Zeldin, MD, corresponding research author, has spent several years studying EETs and their impact on the human body. He and his research group determined that TEEs have beneficial cardiovascular effects, such as lowering blood pressure and inflammation, and improving cell survival after a stroke or heart attack. . However, he pointed out that the involvement of TEEs in the inflammation process can be good or bad depending on the context.

“TEEs can suppress the inflammatory response, which is good, but if they block it too much, it will make macrophages unable to eat the bacteria, which is bad,” Zeldin said.

Edin added that some researchers have tested sEH inhibitors – compounds that prevent sEH from breaking down EETs – in clinical trials to see if they can relieve pain, chronic obstructive pulmonary disease and high blood pressure. He warned that scientists performing these studies are considering the influence of sEH inhibitors on bacterial clearance.

“They have to be careful and stop using them if the person develops pneumonia,” Edin said. “Our study showed that blocking sEH means that TEEs can paralyze macrophages, thereby worsening lung infection.”

Co-author Stavros Garantziotis, MD, medical director of the NIEHS Clinical Research Unit, was instrumental in collecting human macrophages for research.

“Since our study used lung immune cells from healthy volunteers, we are confident that our results are relevant to human health,” said Garantziotis.

Grant number: Z01ES025034

About the National Institute for Environmental Health Sciences (NIEHS): The NIEHS supports research aimed at understanding the effects of the environment on human health and is part of the National Institutes of Health. For more information on the NIEHS or on topics related to environmental health, visit https://www.niehs.nih.gov or subscribe to a news list.

About the National Institutes of Health (NIH):The NIH, the national agency for medical research, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the principal federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit www.nih.gov.

NIH… Transforming Discovery into Health®

The references

Li H, Bradbury JA, Edin ML, Graves JP, Gruzdev A, Cheng J, Hoopes SL, DeGraff LM, Fessler MB, Garantziotis S, Schurman SH, Zeldin DC. 2021. sEH promotes phagocytosis of macrophages and pulmonary clearance of Streptococcus pneumoniae. J Clin Invest: doi: 10.1172 / JCI129679.

###


Source link