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New clues on deadly blood infection

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Scientists have identified an antibody that could “minimise the major internal bleeding seen in traumas like bullet wounds and car crashes”, according to BBC News. The research in question found that mice, primates and humans who had serious blood infections (sepsis) also had high levels of a protein called histone in their blood.

In intact cells, DNA is usually wrapped around this protein, but the newspaper reported that when the cell is damaged the protein is released into the blood, where the scientists believe it can cause internal bleeding by damaging the lining of blood vessel. The researchers found that blocking the actions of histone with an antibody stopped the toxic effects of the protein in mice with sepsis, allowing them to recover from the infection.

This research has identified a potential role for histones in sepsis. Although the results suggested that histones may play a similar role in sepsis in primates, including humans, this is not yet conclusive. One limitation to the study was that it did not state how many baboon and human samples were tested and what proportion of these samples contained histones, which means it is not clear if histones increase in the blood stream in all cases of sepsis. Further research will be needed to confirm the findings in more people with sepsis, and to look at whether histones play a role in other inflammatory diseases.

It is important to note that this study does not indicate whether histones play a role in internal bleeding related to non-inflammatory causes, such as accidents.

Where did the story come from?

Dr Jun Xu and colleagues from the Oklahoma Medical Research Foundation and other research centres in the US carried out this research. Funding sources for the study were not reported, but the researchers themselves were funded by the Howard Hughes Medical Institute, the US National Institutes of Health and the University of Bari, Italy. The study was published in the peer-reviewed journal Nature Medicine.

What kind of scientific study was this?

This was a laboratory study looking at the chemical and biological processes involved in sepsis, a potentially fatal condition where an infection spreads around the body in the blood. This research was mainly in mice, but also looked at blood samples from humans and primates.

Sometimes tissue damage or an infection can trigger the body to mount a strong immune response known as a hyperinflammatory response. The researchers say that this response can sometimes be harmful, as it may contribute to sepsis. The researchers wanted to investigate the hyperinflammatory response to identify related factors that could be targeted by potential new treatments.

White blood cellsare involved in the hyperinflammatory response. the researchers grew mouse macrophages (one type of white blood cell) in a laboratory, activating them by exposing them to bacterial molecules that provoke an immune response. They treated some of these macrophage cells with a drug called APC, which may be used to treat the inflammatory processes in severe sepsis, looking at whether this affected the types of proteins the cells produced. They also looked at whether APC treatment changed how toxic the macrophages were to the cells that line the blood vessels (endothelial cells), as the function of these cells is affected by inflammation and sepsis.

These experiments showed that the APC drug reduced the toxic effect activated macrophages had on the endothelial cells, and that one of the effects of APC was to cause the breakdown of members of a group of proteins called the histones. This finding suggested that the histones might be involved in the hyperinflammatory response and so the researchers concentrated on this group of proteins in their experiments.

The researchers then looked at the effect of histone on endothelial cells grown in the laboratory, and the effect of injecting mice with histone. The researchers took mice that had developed sepsis due to various chemical and surgical causes and gave some of them a mouse antibody that recognises histone. They compared the proportion of mice that died in this antibody treated group to the deaths in the mice left untreated.

The researchers also looked at whether they could identify histones in previously frozen blood samples that had been taken from humans who had sepsis and from baboons infected with a lethal dose of E coli bacteria in previous experiments.

They also looked at:

  • the effects the anti-sepsis APC drug had on histone,
  • whether giving APC injections to mice prevented the toxic effects of a histone injection,
  • the effects that blocking the action of the APC had on mice exposed to bacterial molecules which provoke an immune response, and
  • whether the effects of a provoked immune response could be blocked by giving these mice a mouse anti-histone antibody.

What were the results of the study?

The researchers’ initial experiments suggested that histones were involved in the hyperinflammatory response, and that the drug used to treat sepsis might be having an effect by breaking down these proteins.

They found that the endothelial cells that line the walls of the mouse blood vessels died when exposed to histone in the laboratory, and found similar results in human endothelial cells in the laboratory. Treating these histone-exposed cells with APC reduced the proportion that died. Injecting mice with high levels of histones was fatal, but in five mice injected with APC at the same time as histone, APC prevented the histone injection from causing death.

The researchers found that giving anti-histone antibodies to mice with induced sepsis reduced the proportion of mice that died. When they looked at how the histone injections killed the mice, they found that it caused bleeding into the lungs and small clots to form (thrombosis) in large and small blood vessels. Blocking the action of the APC drug worsened the effect of exposing the mice to bacterial proteins. However, giving these mice an anti-histone antibody blocked these effects.

The researchers found that two baboons infected with E coli had histone protein in their blood and that an increase in the levels of histone in the blood occurred at around the same time as they had developed kidney problems. Two baboons treated with APC had survived and had broken down histone protein in their blood. High levels of histone were also found in some stored blood samples taken from humans with sepsis.

What interpretations did the researchers draw from these results?

The researchers concluded that histones released during sepsis can contribute to cell damage and death, and could be a potential target for drugs to treat sepsis or other inflammatory diseases. They suggest that using a drug that blocks the effect of histones, such as the antibody used in the study, might help patients with sepsis, particularly those that are not suitable for treatment using the drug APC.

What does the NHS Knowledge Service make of this study?

This research has identified a potential role for histones in sepsis, a condition that kills several thousand people a year. The majority of the research was carried out on mice, but some experiments on stored blood samples from baboons and humans with sepsis have also identified histones in their blood. Although the results suggest that histones may play a similar role in sepsis in primates, including humans, this is not yet conclusive. In particular, the researchers did not report how many baboon and human samples they tested, and what proportion of these samples contained histones, so it is not clear if histones are increased in all cases of sepsis. In addition, no control blood samples from humans without sepsis were tested and this research only looked at sepsis and not other diseases.

Overall, it seems that further research will be needed to confirm the findings in more humans with sepsis and to look at whether histones play a role in other inflammatory diseases.

Links to the headlines

Antibody ‘fixes internal bleeds’. BBC news, October 26 2009

Links to the science

Xu J, Zhang X, Pelayo R et al.Extracellular histones are major mediators of death in sepsis. Nature Medicine [published online] October 25 2009

Further reading

Cochrane Review: Human recombinant activated protein C for severe sepsis

Cochrane Reviews: Recombinant human activated protein C for severe sepsis in neonates

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