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Last Updated: Oct 11, 2012 - 10:22:56 PM
Haematology Channel

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Latest Research : Haematology

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Vital discovery may save many from traumatic deaths

Nov 5, 2009 - 3:06:44 PM , Reviewed by: Dr. Rashmi Yadav
Esmon's research has already yielded two FDA-approved drugs.

 
Main results
Extracellular histones released in response to inflammatory challenge contribute to endothelial dysfunction, organ failure and death during sepsis. They can be targeted pharmacologically by antibody to histone or by activated protein C (APC). Antibody to histone reduced the mortality of mice in lipopolysaccharide (LPS), tumor necrosis factor (TNF) or cecal ligation and puncture models of sepsis. Extracellular histones are cytotoxic toward endothelium in vitro and are lethal in mice. In vivo, histone administration resulted in neutrophil margination, vacuolated endothelium, intra-alveolar hemorrhage and macro- and microvascular thrombosis. We detected histone in the circulation of baboons challenged with Escherichia coli, and the increase in histone levels was accompanied by the onset of renal dysfunction. APC cleaves histones and reduces their cytotoxicity. Co-infusion of APC with E. coli in baboons or histones in mice prevented lethality. Blockade of protein C activation exacerbated sublethal LPS challenge into lethality, which was reversed by treatment with antibody to histone. Extracellular histones are potential molecular targets for therapeutics for sepsis and other inflammatory diseases.
[RxPG] Researchers have unravelled how certain proteins can enter the bloodstream and begin to kill the lining of blood vessels, resulting in uncontrolled internal bleeding. Their discovery could help save thousands from traumatic deaths, caused by car crashes or on the battlefield.

Building on this work, Charles Esmon, Oklahoma Medical Research Foundation - cardiovascular biology researcher, and a team of collaborators have discovered an antibody that could counter this deadly process.

'This discovery could open the door to new ways to treat soldiers hurt in IED - attacks, gunshot wound victims and people who suffer a traumatic injury,' said Esmon.

'When we realised that histones were so toxic, we immediately went to work looking for a way to stop their destructive tendencies.' Inside the cells, histones perform an important function, keeping DNA coiled and compressed inside the nucleus.

But the OMRF researchers found that when cells become damaged and burst -- either through injury, infection or diseases such as diabetes -- histones can enter the bloodstream and begin to kill the lining of blood vessels. This results in uncontrolled internal bleeding and fluid build-up in the tissues, which are life-threatening.

Working with Temple University's Marc Monestier, the group discovered antibodies - that can block the histones ability to kill.

'When a patient is suffering from severe bleeds, these antibodies could prevent multi-organ failure,' said Esmon.

The researchers have already tested the antibodies in pre-clinical trials, where they showed promising results and no adverse effects. A potential future step, said Esmon, would be human trials.

Esmon's research has already yielded two FDA-approved drugs.

The findings were published online in Nature Medicine.



Original research article: http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2053.html 
DOI of the scientific paper: 10.1038/nm.2053 
On the web: Supplementary Materials (PDF) 

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 About Dr. Rashmi Yadav
This news story has been reviewed by Dr. Rashmi Yadav before its publication on RxPG News website. Dr. Rashmi Yadav, MBBS, is a senior editor for RxPG News. In her position she is responsible for managing special correspondents and the surgery section of the website. Her areas of special interest include cardiothoracic surgery and interventional radiology. She can be reached for corrections and feedback at rashmi.yadav@rxpgnews.com
RxPG News is committed to promotion and implementation of Evidence Based Medical Journalism in all channels of mass media including internet.
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