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Cell death following blood 'reflow' injury tracked to natural toxin

Researchers at Johns Hopkins have discovered what they believe is the "smoking gun" responsible for most tissue and organ damage after a period of blood oxygen loss followed by a sudden restoration of blood oxygen flow.

Working with mice, the Hopkins team found that the sudden oxygen bath triggered by restored blood flow causes cells to make a chemical so toxic it kills the cells. The work was published in two papers in the Proceedings of the National Academy of Sciences last week.

Although not sure why it happens, the Hopkins scientists believe the toxic chemical, PAR-polymer, acts like a molecular sledgehammer, or a death switch. "We've found evidence of it in cells following all types of injury," says Ted Dawson, M.D., Ph.D., the Leonard and Madlyn Abramson Professor of Neurodegenerative Diseases, professor of neurology and co-director of Hopkins' Neuroregeneration and Repair Program in the Institute of Cell Engineering (ICE).

The research team has named the cell death process caused by PAR-polymer "parthanatos," after Thanatos, the personification of death from Greek mythology.

To establish that PAR-polymer is indeed the culprit in the kind of reperfusion injuries long linked to heart attacks, strokes and a variety of blood vessel injuries, the researchers pumped mouse nerve cells full of PAR-polymer. The cells died, but to be sure PAR-polymer (and not something else) killed them, they examined the brains of mice engineered to lack an enzyme that chews up and gets rid of PAR. These mouse brains contained twice as much PAR-polymer as those of normal mice.

After the researchers induced a blood clot injury like a stroke, the same mice showed a 62 percent increase in the area of brain damage compared to normal littermates. Mice that contain more of the PAR-chewing enzyme suffered less brain damage than their normal littermates.

To figure out what triggers the death switch, the researchers tracked PAR-polym
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Contact: Audrey Huang
audrey@jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions
29-Nov-2006


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