The mouse senses oxygen by skin

Biologists at the University of California San Diego have recently discovered that rats' skin can sense low oxygen levels and regulate the production of erythropoietin (EPO) - the mouse-stimulating hormone produced by cells. Red blood cells help adapt to high environments with low oxygen rates.

This surprising result was published in the April 18, 2008 issue of the Cell's opposition to the view that mammalian skin is a cover that surrounds the body with little contact with the system. steamed.

If it can be applied to humans, discoveries can completely change the way anemia is treated as well as other diseases that require increasing the body's ability to produce red blood cells. It can also be used to increase the resistance of athletes to this summer's Olympics.

Randall Johnson, a professor of biology at the University of California San Diego, led the study. "What we got from the research is quite unusual," says Randall Johnson . We have found that the skin of mammals, or at least the mouse, reacts with the oxygen rate in the external environment . Because of this reaction, blood flow under the skin changes. In contrast, blood flow will change one of the body's most basic reactions to low oxygen levels - the process of producing erythropoietin '.

Scientists believe that this reaction may be a remnant of mammals evolving from lower-grade vertebrates, such as amphibians, with the same type of ion tube to diffuse. oxygen through the permeable skin is like the lungs of mammals.

Johnson adds: 'Amphibians - especially frogs - breathe through the skin and are able to sense and respond to the ratio of oxygen in the air or water surrounding their skin. But no one has ever thought of asking similar questions about mammalian skin. '

According to Frank Powell - a professor of medicine at the University of California San Diego and an expert on the adaptation of animals and humans to the environment above, 'From an evolutionary perspective, results This is perfectly reasonable when it comes to the important role of the skin in the proportion of oxygen absorbed in amphibians. It will be interesting to know how this mechanism works in the human body; How different oxygen levels are felt by the skin can affect how quickly and effectively adapt it to low oxygen levels when people live in high environments or when taking care of especially at the hospital. "

The University of California San Diego team has found no evidence that mice can breathe in the skin. But if you discover mice that sense low oxygen levels by skin and promote EPO production that can be applied in humans, this will be a tremendous discovery for training and Endurance tests of athletes participating in the Summer Olympics in Beijing.

In addition to the two approved methods to increase red blood cell production (high-level training or low-oxygen tents), athletes, swimmers, cyclists and other endurance sports The desire to have better physical strength by increasing the ability of blood to transport oxygen now can have a reasonable method to increase red blood cells. The use of blood doping - injected red blood cells - or synthetic EPO injection to promote red blood cell production is illegal and prohibited during all Olympics and in all sport. But what if athletes can increase their EPO and red blood cells by letting them exercise in an environment with low oxygen levels; or with the same effect, they simply need to increase blood flow through the skin.

According to Johnson, 'We have discovered that a potential physiological thrust can be activated without an exogenous EPO source. In the study, we demonstrated that when we breathe in an environment with certain oxygen levels and let the body expose it to other oxygen levels, it will stimulate the body to produce EPO. It is not difficult to anticipate that people will follow what we learn from mice and apply to humans. '

If our skin is also sensitive to oxygen levels, this could revive the debate around the 'Golden Finger Syndrome '. It can make people remember forever thanks to the famous James Bond movie with details of the criminal's girlfriend being killed after being painted gold. At the same time it is the center of urban myths and internet talk about potential negative effects on the health of leather painting. The Discovery Channel also took this event to conduct two surveys on 'MythBusters'.

The team's discovery was supported by Swedish, German and University of Pennsylvania collaborators. The team obtained results after two years of trying to understand why mice that were genetically manipulated to do experiments had high EPO rates. In 2004, Johnson and his students posted an article in the Plos Biology explaining in detail how they transformed a normal experimental mouse into a tolerant 'gnawing' athlete. Olympic athletes. They did this by eliminating the gene that causes mammalian muscles to shift from gas-exchange to anaerobic metabolism when the oxygen rate in the muscle drops.

Most of our daily activities require air to be carried out, the biochemical mechanism in the muscle takes full advantage of oxygen. But when the needs of the muscle system exceed the available oxygen supply, such as running a bus or lifting a heavy object, the protein called HIF-1 (hypoxia inducible transcription factor-1) is activated. . It allows muscles to switch to a more powerful mode - anaerobic metabolism - without using oxygen but releasing lactic acid as a byproduct.

When Johnson and his students removed the operating section of the HIF-1 gene, they created tiny mice with delicate red skin. These mice have problems keeping body heat because most of the blood is taken to the skin and cooled, just like the person sitting in a sauna. But the most surprising thing in the major mutant mice is their unusually high EPO rate - 90% of the serum is red blood cells while the average is only 40% to 50%.

Johnson said: 'Their blood is slightly viscous and heart, consequently, increases in size. We cannot understand why the skin has this effect. We have no concept about it. We can know every aspect around why the mutant mouse looks like that, acts like that. But that really confused us and we went towards this research. When we discovered EPO was born from the inner organs, not the skin of the mouse; We thought surely there must be a signal from the skin to the body inside the body. '

Johnson and his colleagues worked at his lab - including graduate student Adam Boutin, postdoctoral fellow Alexander Weidemann and student Lernik Mesropian - who confirmed that the HIF-1 gene plays a decisive role in How to conduct gene manipulation in mice mutant without HIF-1 gene in skin cells. Those mice could not signal the production of additional EPO when their skin was surrounded by a 10% oxygen environment (equal to the ratio on Mount Everest). Oxygen levels in the sea are about 21%. Normal mice can still increase EPO production if the oxygen ratio is at 10%.

The researchers also found that the reaction occurs when more blood reaches the skin. When placed on rat skin nitroglycerine patches with the effect of increasing excessive blood flow, they found that mice could significantly enhance the production of EPO and red blood cells.

'EPO control will bring a billion-dollar pharmaceutical market to treat all diseases associated with low red blood cell counts. So the ability to control the production of red blood cells by changing blood flow through certain parts of the skin is of great significance. In the study, we have shown that just putting a small nitroglycerine patch can stimulate EPO production with great intensity. Even so, we are not sure whether this finding is true for humans. But obviously this is a very interesting way to control this signal line, ' Johnson said.

Scientists exposed the head and body of the mouse to an independent mixture of 10% oxygen (equal to the ratio on Everest) and a mixture of 21% oxygen (ratio in seawater).(Photo: University of California - San Diego)

Johnson and his team - including assistant professor of biology Colin Jamora of the University of California San Diego - found that mice with the entire exposed body in a low oxygen environment had the strongest response. as well as producing the most EPO. While the mice that were breathing in a room had only 10% oxygen, the skin from the neck down came into contact with the air in another room with an oxygen ratio of 21% (oxygen ratio. in seawater, the ability to adapt to low oxygen environment is reduced by 1.5 times.

Johnson said: 'If we put mice lacking hypoxic reactions in the skin into a low-oxygen room, their hypoxic reaction is reduced by more than half, and this is amazing to us. The skin is a major contributor to how mice react to low oxygen levels. '

Powell said: 'All of the important reactions to hypoxia (or low oxygen rates) have previously been thought to be stimulated by the nervous system and oxygen-sensitive molecules in the blood as well as the internal organs. . But our experiments clearly demonstrated that the skin reacts directly to changes in oxygen levels in the environment by changes in blood flow. Transforming the blood flow in the skin has a big role in HIF ratio conversion, which works just like a switch to adapt to low oxygen rates. It activates many genes that increase the ability to transport oxygen to parts of the body. '

According to Johnson, because people with skin diseases such as psoriasis or eczema have low RBCs, he and his team are very interested in expanding their research to understand anemia caused by inflammation. Skin causes in mutant mice.

He added: 'It seems that EPO in people with anemia due to inflammation has no effect. In fact, we have mutated mice with skin infections that have a similar condition. They have a high EPO rate, but not a red blood cell ratio. The mutant mice used in the study had a high EPO ratio and a high rate of erythrocytes but without skin infections. In the next step, we will investigate why skin infections cause EPO production. Is there something in these diseases that we can use to treat patients without suffering from anemia? '

The study also explains why people in some areas in Nepal, India and Pakistan take baby mustard oil on newborn babies. This is a harmless stimulant that can enhance blood flow through the skin.

Johnson said: 'In our study, we have shown that if you apply a stimulant to the skin of mustard oil, it can also increase EPO production even though the ratio is quite low. Children in some Indian and Pakistani communities were rubbed with mustard oil at birth. Some health advocates have tried to advise people to abandon this tradition. But we have shown that mustard oil increases EPO ratio in mice. As the EPO rate increases, the rate of red blood cells increases. And we can fully imagine its benefits. '