Breathing Is Skin Deep

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Biologists from the University of California, San Diego, have discovered that the skin of mice can sense low levels of oxygen and accordingly regulate the production of erythropoietin, or EPO, which is the hormone responsible for producing red blood cells and adapting to high altitude.

The surprising report, published in the April 18 issue of the journal Cell, challenges the conventional thinking that mammalian skin acts as a kind of envelope for bodies, disparate from the respiratory system. If the finding holds true for humans, it could change how physicians treat anemia and other red-blood-cell diseases, and would have major implications for endurance athletes.

“What we found in this study is really something quite unusual,” said Randall Johnson, a professor of biology at UC San Diego who led the study. “We discovered that mammalian skin, at least in mice, responds to how much oxygen is above it and, by virtue of that response, changes blood flow through the skin.”

Even more remarkable, the researchers believe that this is an evolutionary trait retained in mammals as they evolved from lower forms, such as amphibians, who can promote oxygen diffusion through their very permeable skins. However, the UC San Diego team found no evidence that mice could actually breathe through their skin.

The study’s implications for endurance athletes — like those at this summer’s Olympic Games in Beijing — are profound. Blood doping, an injection of additional red blood cells, and the injection of synthetic recombinant EPO are illegal in the Olympics and generally banned by sports’ governing agencies. But could athletes increase their red-blood-cell counts and EPO by treating their bodies to low levels of oxygen?

If human skin indeed behaves similarly to mouse skin, it could also spark a renewed debate over the validity of “Goldfinger Syndrome,” so-called because the villain’s girlfriend in the seminal James Bond film dies as a result of being painted gold from head to toe.

“We’ve discovered a potent physiological trigger that can be enacted or enabled without exogenous sources of EPO,” Johnson said. “We show in this paper that breathing in one level of oxygen and exposing your body to another level of oxygen is really a potent trigger for the body to produce its own EPO. It’s not hard to foresee people taking what we’ve learned in mice and applying it to humans.”

Johnson is interested in extending the study to investigate anemia and skin inflammations such as psoriasis and eczema, which can involve low red-blood-cell counts.

“In people with anemia or inflammation, it seems as if the EPO isn’t having an effect,” Johnson said. “We actually have mutant mice with skin inflammation that show this same effect. They have high EPO levels, but they don’t have a high red-blood-cell count. The mutants we used in our study have high EPO levels and high red-blood-cell counts. But they don’t have inflammation.

“The next step for us is going to be trying to figure out why these inflammatory diseases trigger EPO. Is there something about inflammation that we can trigger so these people can be treated without suffering this kind of anemia?”

In their paper, the researchers also made mention of traditional practices in some areas of Nepal, India and Pakistan, where parents massage newborn babies in mustard oil, which promotes blood flow through the skin.

“We show in this study that if you paint the skin of a mouse with this mild irritant, mustard oil, it will also trigger EPO release at a somewhat lower level,” Johnson said. “In India and Pakistan, babies are in some communities massaged in mustard oil at birth; and some health workers have been trying to get them to stop this folk tradition. But we show that in mice this increases EPO levels. And since increased EPO levels contribute to increased red-blood-cell counts, one could imagine it being beneficial.”

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