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November 2, 2009
Histones Play Role in Sepsis
In a surprising finding, histones, which help pack DNA into chromosomes, were tied to the life-threatening illness sepsis. The proteins are now potential molecular targets for treating sepsis and other inflammatory diseases.
Sepsis is a caused by the body's immune system going into overdrive, usually because of an infection. It causes inflammation and small blood clots, blocking blood flow to vital organs and leading to organ failure. A quick diagnosis is crucial, because 1 of every 3 people who get sepsis die from it.
A synthetic form of activated protein C (APC), which inhibits clots and inflammation in the human body, is the only drug approved by the U.S. Food and Drug Administration for treating severe sepsis. With the hope of gaining insight into designing more effective treatments for sepsis, a team led by Dr. Charles Esmon at the Oklahoma Medical Research Foundation set out to gain a better understanding of how APC works. The investigation was funded by NIH's National Institute of General Medical Sciences (NIGMS), the Howard Hughes Medical Institute and the University of Bari, Italy.
The team began by examining proteins in cell cultures that had been treated with APC. As reported online on October 25, 2009, in Nature Medicine, APC treatment caused 3 new bands to appear on protein gels. Sequencing of the proteins revealed that they were portions of histones. Histones are the structural supports around which long DNA strands are wound to make a more compact shape.
The researchers confirmed that APC cleaves histones. They also found that, while adding histones to cell cultures causes extensive cell damage, APC helps protect the cells. These experiments implied that APC may protect against sepsis, at least in part, by cleaving histones. To test the idea, the researchers turned to some frozen baboon blood plasma.
Years ago, Esmon's team worked on the development of APC to treat sepsis, using baboons to study APC's effects. The animals had been rescued with APC after receiving lethal levels of the bacteria E. coli to produce septic shock. When the researchers examined the frozen blood samples collected during those experiments, they found higher levels of histones during septic shock and cleaved histones in baboons treated with APC. They also detected cleaved histones in samples from at least 1 human treated with APC.
The researchers directly tested whether histones play a role in sepsis by injecting histones into mice to cause lethal sepsis. APC rescued mice given a lethal dose of histones, as did an antibody that bound to histones.
During a serious infection, cells are damaged, causing histones to be released into the blood stream. "People had seen histones out in the circulation before and they'd say, 'So what?' But it wasn't so what. These guys are really bad players," Esmon says.
The researchers plan to look for histones in the blood of patients with autoimmune disease such as lupus or type 1 diabetes, as well as any disease with major complications in blood vessels, such as myocardial infarction and reperfusion injuries. A drug that could block histones may have promise for more than septic shock patients.
—by Harrison Wein, Ph.D.