(From the February 2014 issue of Research Now)
Clinician scientists in The Research Institute at Nationwide Children’s Hospital have found a potential new treatment for lung injury that can result from breathing high levels of oxygen—a treatment often required in intensive care settings. The drug, already approved for rheumatoid arthritis due to its anti-inflammatory properties, increased survival time five-fold and reduced damage to lung tissue in mice. The results were published in December in the journal Antioxidants & Redox Signaling.
Critically ill patients, including premature infants, often suffer from a variety of complex medical problems and need additional oxygen. In this treatment, called hyperoxia, high levels of oxygen are given to increase oxygen delivery to tissues and organs. Over time, however, hyperoxia can lead to inflammation and even the death of lung tissue. It also has been implicated in bronchopulmonary dysplasia (BPD) and developmental delays in neonatal intensive care unit (ICU) patients.
“Knowing that hyperoxia causes lung injury, clinical care in the ICU is increasingly focused on determining and using the minimum amount of oxygen necessary to achieve adequate tissue oxygenation,” says Trent Tipple, MD, principal investigator in the Center for Perinatal Research at Nationwide Children’s and senior author of this new study. “We want to prevent the adverse effects of hyperoxia, and an existing rheumatoid arthritis drug, aurothioglucose (ATG), decreases inflammation and activates pathways that enhance the production of antioxidants in lung tissues.”
In the latest of a series of studies examining lung injury in mouse models, Dr. Tipple and colleagues demonstrated that the arthritis drug ATG attenuates lung damage and enhances survival in lung injury induced by inflammation and hyperoxia.
When too much oxygen is present in the lungs, as in hyperoxia, it triggers a pathway of reactions that results in the loss of an antioxidant called glutathione (GSH), which is crucial to the maintenance of healthy lung tissue. GSH depletion contributes to fluid build-up in the lungs, cell and tissue death and worsened lung injury, which can lead to acute respiratory distress syndrome.
Dr. Tipple and his team found that a dose of ATG administered to mice with inflammatory lung injury helped boost their levels of GSH, preserve lung tissue and significantly increase survival in hyperoxia compared to untreated mice. The drug appears to work by activating pathways that enhance the production of GSH. If GSH production was blocked, the drug’s effectiveness was lost.
“An advantage for ATG and other similar drugs is that they are already approved by the Food and Drug Administration for other indications,” says Dr. Tipple, who also is an assistant professor of Pediatrics at The Ohio State University College of Medicine. “While additional preclinical studies are needed prior to starting clinical trials in critically ill human patients, translating preclinical findings into human clinical trials will theoretically be more quickly accomplished using an approved medication.”
The primary focus of Dr. Tipple’s lab is to identify clinically relevant therapies to prevent BPD in premature infants. In addition to lung antioxidant defenses, ATG also activates specific pathways that are critical in newborn lung development and that are disrupted in patients with BPD.
His lab is currently examining the effectiveness of ATG in mouse models of BPD. The team posits that, by activating a patient’s own antioxidant responses in the lungs, patients can protect their lungs against hyperoxia more effectively than by taking antioxidants like a medicine. In time, Dr. Tipple says, research on these mouse models could translate to improvements in clinical care in patients exposed to hyperoxia.
Britt RD, Velten M, Locy ML, Rogers LK, Tipple TE.The thioredoxin reductase-1 inhibitor aurothioglucose attenuates lung injury and improves survival in a murine model of acute respiratory distress syndrome. Antioxidants & Redox Signaling. 2013 Dec 2. [Epub ahead of print].
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