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【bio-news】Cell death following blood 'reflow' injury trac
Contact: Audrey Huang
audrey@jhmi.edu
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Johns Hopkins Medical Institutions
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.
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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.
On the Web: http://www.neuroice.org/
http://www.eurekalert.org/pub_releases/2006-11/jhmi-cdf112906.php 本人已经认领此文. 如在48小时内未能提交译文, 其他战友可自由认领 细胞固有毒素造成血液“返流”损伤后的细胞死亡
在缺血一段时间后，快速恢复正常氧供应，约翰•霍普金斯研究者发现一种新物质，能够引起大部分器官组织的损伤
研究者在小鼠实验中发现恢复血流量引起的快速氧气浴造成了细胞产生毒性物质能够杀伤细胞，这次实验写成两篇文章发表在上个星期的国家科学院院报中。
尽管难以确定其发生机制，约翰.霍普金斯的研究者认为这种毒性物质PAR-polymer对细胞膜有裂解作用或者是死亡电闸，医学和药学博士Ted Dawson以及神经变性疾病教授、神经病学教授、霍普金斯ICE神经再生和修复程序共同主管者Leonard 和Madlyn Abramson宣称已找到 PAR-polymer对细胞各种类型损害的依据。
研究小组对PAR-polymer引起的死亡命名为“parthanatos”，是在Thanatos（死）之后，对希腊神话的死亡说法又一种拟人化。
为了证实PAR-polymer的确是由再灌注损伤引发心脏病、中风以及各种血管损伤的“罪魁祸首”，研究者在鼠神经细胞中注入大量PAR-polymer，细胞发生死亡。但为了进一步确定是由PAR-polymer而非其它物质引起的细胞死亡，他们设计一种缺乏PAR裂解酶的小鼠，发现其脑中PAR-polymer含量是正常小鼠的两倍。
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作者:admin@医学,生命科学 2011-04-27 05:11
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