People with breathing dysfunction may find better treatment options now thanks to the findings of a recently published University study.
Dr. Benjamin Gaston, a pediatrician and researcher at the Medical School, completed a study published in the science journal Nature about an enzyme believed to be responsible for abnormal responses to a lack of oxygen in the blood. This research focuses on a molecule called S-nitrosothiol, or SNO, and explains how it alerts the brain stem about irregularities in oxygen amounts in the lungs. If there wasn't enough oxygen in the lungs, the molecule would send a message to the brain, triggering the brain to respond by making the lungs breathe faster, or forcing blood vessels to dilate.
The study also says SNO is responsible for regulating the rate and depth of breath and blood vessel dilation. Gaston says this molecule has far-reaching significance. It can explain everything from how mountain climbers' bodies counteract altitudes where there is little oxygen to how football players react to late-game strain.
"If a U.Va. quarterback is playing in the fourth quarter and begins feeling strain in his quadriceps, the SNO will help to dilate blood vessels in the leg so the player can continue," Gaston said.
This study was completed in cooperation with Chemistry Department Chairman Timothy McDonald, and graduate student Michael Johnson. It has challenged previously held scientific opinion that have tried to explain abnormal responses to hypoxia, or a decreased amount of oxygen in the blood. Large molecules called hemoglobin, which transport oxygen through the body, were earlier thought to be responsible for the regulation of breathlessness. But Gaston's study suggests SNO, a compound found in the blood and the lungs, does this.
To explore this compound and its function, the researchers needed to experiment on two levels-the biochemical level and the animal model level. Gaston and his colleagues first worked on the molecular level. They investigated the avenues of SNO production, synthesized SNO compounds that was in blood with normal oxygen saturation and blood with hypoxia (only 10 percent oxygen saturation), and extracted the SNO compounds from the normal and hypoxic blood.
Afterward, Gaston sent the samples to a colleague, Pediatrics and Physiology Prof. David Gozal of Tulane University, for the second phase of the experiment-the animal model level. Through the use of rats, they found that the SNO compounds needed to be small to function in the brain. Therefore a "chopping enzyme" had to be present as well. This explains why rat models that had SNO but no the "chopping enzyme" had the same response as a newborn in respiratory failure, Gaston said. However, when the SNO compounds were "chopped" into a minute enough form, the brain responded correctly to the hypoxia, supporting Gaston and his team's hypothesis about SNO's importance.
"This is one of many recent works that make it increasingly apparent that complex biological systems have been brilliantly conceived, are intelligently integrated and are unlikely to have been created by chancealone," Gaston said.
The applications of this new knowledge to science and health care are expansive.
Gaston says that his discovery will lead future treatment of hypoxia in a new direction.
According to him, current treatment options for patients who have difficulty breathing are inadequate. Doctors in the past have used chemicals such as caffeine, primarily with infants, and theophylline, a drug which may be dangerous for certain patients.
He added that other treatments for apnea, or cessation of breathing, could cause problems.
"More commonly, mechanical devices like ventilators or other breathing machines are used, and they are cumbersome, invasive and expensive. For these reasons, there is much interest in developing a better course of treatment. The hope is that compounds can be generated to help people having respiratory failure due to poor brain stem response and [these generated compounds] can decrease need for mechanical ventilation," Gaston said.
This study also has implications beyond treatment. Work on this topic gave researchers in the Medical School a rare chance to work with College faculty through research collaboration, a practice that McDonald notes is "the wave of the future."
McDonald's work in the College focused on measuring and characterizing the SNO molecule and exploring its mechanisms of transfer and transformation. Because his work in the College was combined with Gaston's in the Medical School, this gave the study a different and more balanced approach on the topic.
"Problems in biology are increasingly being understood and examined at the molecular level," McDonald said. The School of Medicine and College of Arts and Sciences "bring different perspectives to a problem, each perspective enhancing the other." According to McDonald, Gaston stitched together a program that integrated the molecular view and the whole animal."
For the millions of people suffering from disorders of respiration, this new research lends possibility and hope, and may offer more options for patients with severe breathing problems.
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