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 Johns 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 recently in two papers in the
Proceedings of the National Academy of Sciences.
Although not sure why it happens, the scientists
believe that 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,"
said Ted Dawson, 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.
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 the journey of PAR-polymer 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, said Valina Dawson, 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 said.
Researchers were supported by grants from the National
Institutes of Health and the American Heart Association.
In addition to Valina Dawson and Ted Dawson, 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 and
Patricia Hurn, all of Johns Hopkins; and Guy Poirier, of
Laval University Medical Research Center at Centre
Hospitalier Universitaire de Quebec in Canada.
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