X-Message-Number: 28731
From: "Basie" <>
Subject: Cell Death Following Blood 'Reflow' Injury Tracked To Natural...
Date: Fri, 8 Dec 2006 18:07:22 -0500

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-polymer's journey after cells made it. After 15 minutes, PAR-polymer 
hadn't gone anywhere. But after 30 to 60 minutes, the researchers discovered 
that much of it traveled right to areas where the switch normally resides.

The fate of the cell is irreversible once PAR-polymer sets off the trigger, 
says Valina Dawson, Ph.D., professor of neurology, co-director of the 
Neuroregeneration and Repair Program and author of the papers. "If we could 
figure out how to block PAR-polymer, we could design drugs that protect the 
switch and prevent cells from dying after heart attacks, stroke or other 
injuries," she says.

Researchers were supported by grants from the National Institutes of Health 
and the American Heart Association.

Authors of the two papers are Shaida Andrabi, No Soo Kim, Seong Woon Yu, 
Hongmin Wang, David Koh, Masayuki Sasaki, Judith Klaus, Takatshi Otsuka, 
Zhizheng Zhang, Raymond Koehler, Patricia Hurn, Valina Dawson and Ted 
Dawson, all of Hopkins, and Guy Poirier of Laval University Medical Research 
Center at Centre Hospitalier Universitaire de Quebec in Canada.

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