February 7, 2003

High-intake oxygen can be harmful: VUMC study

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Dr. Jack Roberts, right, and Joshua Fessel are leading the VUMC study of the harmful effects of oxygen.(photo by Dana Johnson)

High-intake oxygen can be harmful: VUMC study

At health spas, mall kiosks, and “oxygen bars” across the country, people are paying to breathe oxygen. For about a dollar a minute, enthusiasts inhale 95 percent oxygen — air offers a paltry 21 percent O2 — and report that it relieves a variety of maladies from hangovers to headaches.

The practice may be a bad idea, according to Vanderbilt University Medical Center scientists who are studying the damaging effects of free radicals — highly reactive molecules derived from oxygen.

“We’re starting to think that oxygen is not as benign as many believe it is,” said Dr. L. Jackson Roberts II, professor of Pharmacology and Medicine.

Roberts and Joshua P. Fessel, an M.D./Ph.D. student, have discovered a new class of compounds, called isofurans, which form when free radicals attack cell membrane lipids. Isofurans, whose production is favored by high oxygen concentrations, are expected to be a useful tool for assessing the role of free radicals and oxidative injury in disease and for evaluating the effectiveness of antioxidant therapies.

Already, the investigators have demonstrated that isofuran levels increase when animals breathe 100 percent oxygen for as little as three hours. These findings, part of the group’s work reported in the Proceedings of the National Academy of Sciences, demonstrate that free radical processes are at work in hyperoxia-induced lung injury. “We suspected this to be the case, but we didn’t have the tools to show it until now,” Roberts said.

Hyperoxia-induced lung injury is a key problem in intensive care units. Patients on ventilators can only breathe oxygen concentrations up to 60 percent for prolonged periods of time. Higher concentrations — though of potential benefit to the body’s organs — lead to severe lung damage.

The ability to measure isofuran production will make it possible to study the oxygen-induced damage and to evaluate potential therapeutic interventions like antioxidants, the researchers said.

“The question is, is there something we can do that would allow clinicians to actually use higher concentrations of oxygen safely, and therefore better oxygenate patients who are sick?” Roberts said. “We don’t know yet, but now we have a way to monitor that.”

The fact that isofuran levels increased in the lung after only three hours of exposure to 100 percent oxygen — indicating that free radical damage is a very early event — surprised the researchers. They also found evidence for the release of a trigger for programmed cell death, cytochrome c, in the lung at three hours.

“Most physicians are certainly aware that extended periods of exposure to 100 percent oxygen is harmful, but three hours would not be considered an extended period of time,” Fessel said. The short time frame of free radical damage opens questions about potential damage to the lungs of patients who breathe 100 percent oxygen during surgical procedures and to the lungs of those “oxygen bar” enthusiasts.

For a healthy individual, any damage that results from breathing high concentrations of oxygen for a short time is likely to be insignificant and spontaneously repaired, Fessel said. “But what about the person who has some underlying infection or other problem in the lung?” he asked.

Roberts and colleagues, including Dr. Jeffrey Balser, James Tayloe Gwathmey Professor and Chair of Anesthesiology, and Dr. Kenneth Smithson, assistant professor of Anesthesiology, are launching a clinical study to evaluate how free radical processes might impact lung function in surgery patients. The study could suggest that lower oxygen levels would be beneficial, Roberts and Fessel said, or that antioxidant interventions should be tested to prevent free radical damage.

The newly identified isofurans are actually the second set of compounds that Roberts and colleagues have linked to free radical processes. The group’s 1990 discovery of isoprostanes, prostaglandin-like products of free radical injury, made it possible for researchers to detect and monitor free radical reactions in human beings for the first time. Measuring isoprostanes quickly became the “gold standard in the field,” Roberts said, and it has been used to implicate free radicals in disease processes ranging from atherosclerosis to neurodegeneration.

But isoprostanes are not perfect measures of free radical processes. Because the formation of these compounds becomes disfavored when oxygen levels climb above 21 percent, they do not provide an accurate measure of free radical reactions that occur in the presence of high oxygen concentrations. The isofurans overcome this limitation. High oxygen levels favor the chemical reactions that produce isofurans, making them useful indicators of free radical damage in high oxygen settings like hyperoxia-induced lung injury, as the investigators showed, and for other oxygen-associated disease states like retinopathy of prematurity.

The investigators also have measured isofurans to assess oxidative injury in disease states involving mitochondrial dysfunction. Mitochondria — the power plants of cells — use oxygen in a complex series of energy-generating chemical reactions. They also generate free radicals. When mitochondria are not fully functional, oxygen levels inside the cell theoretically climb. Roberts and Fessel postulated that free radical activity under these conditions might result in isofuran production.

Indeed, they found that isofuran levels were elevated in brain tissue samples from Parkinson’s patients —Parkinson’s disease is known to involve mitochondrial dysfunction —whereas isoprostane levels were unchanged. The investigators will continue to explore disease states where mitochondrial dysfunction is thought to play a role.

“Measuring isofurans really complements measuring isoprostanes,” Roberts said. “Together the two of them provide a complete picture of oxidant stress.”

The two also can serve as a sort of “oxygen sensor,” Fessel and Roberts said. The researchers found that the ratio of isofuran to isoprostane concentrations in normal tissues — the compounds are produced by ongoing free radical processes — provides an indication of tissue oxygenation. In oxygen-rich tissues like brain and kidney, isofuran levels were two to three times higher than isoprostane levels. In the oxygen-poor liver, isoprostanes predominated.

“The isofuran/isoprostane ratio is really a measure of steady state tissue oxygenation,” Fessel said. The ratio should be useful for studying disease states where oxygen supply is perturbed, like peripheral vascular disease, or for assessing the effectiveness of so-called “blood substitutes” — compounds that carry oxygen to tissues, he said.

Other authors of the PNAS study include Ned A. Porter, Ph.D., Stevenson Professor of Chemistry, Dr. James R. Sheller, associate professor of Medicine, and Dr. Kevin P. Moore of the Royal Free and University College Medical School in London. The work was supported by the National Institutes of Health and the PhRMA Foundation.