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Study shows pathway that can destroy healthy cells, leading to organ damage

David Templeton, Pittsburgh Post-Gazette on

Published in Health & Fitness

PITTSBURGH -- A University of Pittsburgh study fully describes for the first time an important but complicated cell-death pathway that can destroy healthy cells, resulting in tissue and organ damage.

The pathway is responsible for a serious asthma attack, excess traumatic brain damage and kidney failure, among other health problems.

Published online Thursday in the journal Cell, the Pitt study identifies a key protein in the cell-death pathway known as ferroptosis, typically a healthy and necessary process that uses iron to kill already damaged or malfunctioning cells then recycles them safely and efficiently.

That protein -- PEBP1 -- serves as the pathway warden in controlling whether a certain enzyme, 15LO, ends up making a fat molecule or lipid, OOH-Pes, in such volumes that they signal the activation of the cell-death process.

With the study now describing the entire process, Pitt researchers already are working to design drugs to prevent the warden protein and enzyme from combining, with the goal of halting cell destruction.

"Better treatments for traumatic brain injury and acute kidney injuries are desperately needed," stated Hulya Bayir, research director of Pediatric Critical Care Medicine at Children's Hospital of Pittsburgh of UPMC, and a researcher in the study.

The study's senior author Valerian Kagan, a professor in Pitt's Graduate School of Public Health's Department of Environmental and Occupational Health, was key in discovering the protein's important role in the cell-death process.

Sally Wenzel, a professor of medicine in Pitt's School of Medicine and director of the University of Pittsburgh Asthma Institute at UPMC, led the study with her focus on the possible pathway leading to asthma exacerbation.

For some people with asthma, she said, a virus, air pollution or even cigarette smoke can trigger oxidative stress, which among other effects, could inhibit a good protein necessary to control cellular mucus production. With that protein suppressed, dangerous lipids likely would be generated that signal the cell-death process. One potential result is the destruction of mucus-producing airway cells, that could cause them to release their entire supply of mucus into the airways. Resulting airway restrictions can require emergency treatment, she said.

"Asthma is not just about stopping an attack, it's also about preventing them -- and both are a major unmet need among patients," Dr. Wenzel said in a statement. "Our study identifies how ferroptotic death signals can damage the cells lining the airway. Targeting these pathways could lead to preventative and treatment options for asthma exacerbations."

Disease, injury and certain environmental triggers can lead to Inflammation (friendly fire from the immune system) and oxidative stress caused by excessive free radicals in the body. Both can initiate ferroptosis.

Treatments now can be designed to block the newly discovered protein-enzyme complex. The Pitt study also describes variations in that pathway leading to a serious asthma attack, neuron damage from brain injuries and renal failure in kidney disease.

Sally Wenzel, a professor of medicine in Pitt's School of Medicine and director of the University of Pittsburgh Asthma Institute at UPMC, led the study with her focus on the likely possibility that the pathway could be leading to asthma exacerbation.

For some people with asthma, she said, a virus, air pollution or even cigarette smoke can trigger oxidative stress, which among other effects, could inhibit a good protein necessary to control cellular mucus production. With that protein suppressed, dangerous lipids likely would be generated that signal the cell-death process. One potential result is the destruction of mucus-producing airway cells, that could cause them to release their entire supply of mucus into the airways. Resulting airway restrictions can require emergency treatment, she said.

"Asthma is not just about stopping an attack, it's also about preventing them -- and both are a major unmet need among patients," Dr. Wenzel said in a statement. "Our study identifies how ferroptotic death signals can damage the cells lining the airway. Targeting these pathways could lead to preventative and treatment options for asthma exacerbations."

Scott Dixon, a Stanford University professor of biology, said the study, in which he was not involved, is "quite important" in finding that an already known protein, quite unexpectedly, plays a key role in cell death.

"No one even anticipated that a protein needed to be involved," he said, noting the good news that its involvement means that the cell-death pathway is well organized and not a spontaneous thing, as some had speculated. "Any time something is organized in a cell, you can think of ways to interfere with it. It means there are new ways to use a drug to inhibit cell death."

(c)2017 Pittsburgh Post-Gazette

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