Using zebrafish because they have similar genes to humans, US researchers discovered that hydrogen peroxide, the chemical that we use to bleach hair and clean and disinfect wounds, appears to play an important natural role in the way our bodies respond to injury: it pulls the emergency cord that causes the immune system to summon white blood cells to the aid of wounded tissue.

The study was led by a team from Harvard Medical School in Boston, Massachusetts, USA, and was published in the 3 June issue of Nature.

Scientists already knew that white blood cells made hydrogen peroxide to kill bacteria, but this is the first clue that the molecule also behaves like a “first responder” on the scene of injury that gives rise to the alarm that trauma has occurred. We don’t know know much about how tissue cells signal when there has been damage, hence the importance of this discovery.

The researchers hope the discovery will help us better understand conditions like asthma which are characterized by higher levels of hydrogen peroxide and white blood cells in the affected tissue.

The research was done in the labs of Harvard Medical School systems biology professor Timothy Mitchison and Dana Farber Cancer Institute professor Thomas Look and discovered that when the tail fins of zebrafish are injured the burst of hydrogen peroxide occurs at the wound and surrounding tissue and then white blood cells make their way to the site and start working.

Mitchison said:

“It’s really a spectacular piece of biology because these cells detect the wound at some distance.”

They had already seen this happen before but were mystified as to what the white cells were responding to.

“We do know something about what summons white blood cells to areas that are chronically inflamed, but in the case of an isolated physical wound, we haven’t really known what the signal is,” he explained.

When two postdoc researchers, Philipp Niethammer in Mitchison’s lab, and Clemmens Grabber in Look’s lab started the investigation they weren’t interested in wound healing: they were looking more generally at how to detect reactive oxygen species (ROS) molecules in organisms (hydrogen peroxide is a type of ROS molecule).

They were using hydrogen peroxide to trace the location of ROS molecules in zebrafish. Using a gene engineered to change color when hydrogen peroxide was present, they inserted it into zebrafish embryos. The idea was that as the embryos grew the gene spread throughout their bodies so that where hydrogen peroxide was present then that part of the body would “glow”.

The researchers already knew that making a small wound on the fish would bring white blood cells and they also knew that where there were white blood cells there was hydrogen peroxide, so they inflicted small wounds on the fish and waited to see what happened.

Much to their surprise, the wounded sites started to glow before the white blood cells arrived, and the glow spread to surrounding tissue as well, showing that hydrogen peroxide did not arrive with the white blood cells but was there beforehand.

So they repeated the experiment by first disabling the ability of the zebrafish to make hydrogen peroxide (they switched off a protein that is known to produce hydrogen peroxide in the human thyroid gland). When the wound was inflicted this time there was no glow, indicating that the hydrogen peroxide was not present. Also, no white blood cells appeared at the wound site showing that they had not been summoned.

Niethammer said:

“This was our real eureka! moment.”

“We weren’t too surprised that we could block hydrogen peroxide production through this technique, but what we didn’t expect at all was that white blood cells wouldn’t respond,” he explained, adding that, “this proved that the white blood cells ‘needed’ hydrogen peroxide to sense the wound, and move towards it”.

Although zebrafish share some genes with humans the researchers will still need to show that this property is preserved in humans before they can be sure it also happens in our bodies, where hydrogen peroxide is known to be produced in the lungs, guts and thyroid.

Perhaps if they do this then it may go some way to explaining why conditions linked to excessive white blood cells in these parts of the body develop, for instance diseases like asthma, chronic pulmonary obstruction and some inflammatory gut conditions.

“It’s very logical that both those tissues produce hydrogen peroxide all the time,” said Mitchison, suggesting that perhaps in conditions like asthma the tissue produces too much hydrogen peroxide because the irritation is chronic, and this may explain why there are too many white blood cells there.

Mitchison has already started planning this next stage of research.

“A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish.”
Philipp Niethammer, Clemens Grabher, A Thomas Look, and Timothy J Mitchison.
Nature advance online publication 3 June 2009.

Source: Harvard Medical School.

Written by: Catharine Paddock, PhD