When babies arrive early, everything about them is under-developed—including their lungs. The premature exposure to higher levels of oxygen (hyperoxia) outside the womb, coupled with medications and therapies that enable these preemies to survive, can cause serious damage to lung tissue. In up to 10,000 babies each year, these circumstances lead to a chronic lung disease called bronchopulmonary dysplasia, or BPD. Enter Trent Tipple, MD, principal investigator in the Center for Perinatal Research at The Research Institute at Nationwide Children’s Hospital, and his colleagues, who are working together to help fight BPD in premature babies being cared for each year.
“One of the main problems encountered by prematurely born infants is that they’re exposed to hyperoxia—they’re over-oxidated,” Dr. Tipple says. Despite this challenge, basic research on lung development is uncovering some promising results. Dr. Tipple’s lab studies mice with lungs that resemble the lung development of babies born at 26 weeks gestation, with and without oxidative stress. This allows them to understand what happens to lung cells under different conditions, as well as which therapies may help human infants build healthier lung tissue. Their current focus is on the thioredoxin system.
“The thioredoxin system is commonly thought of as an antioxidant system. We’re trying to figure out a way to help babies help themselves, not by treating them with antioxidants, but by targeting the thioredoxin system to try to help their bodies increase the production of their own antioxidants,” says Dr. Tipple. If they can manipulate this system in babies, they may be able to stimulate the infants’ creation of protective antioxidants to help them avoid damage from hyperoxia. One way to jump-start this self-protection may even be a drug already in existence.
“We’re finding that an arthritis drug, called aurothioglucose, given to mice prior to going into hyperoxia may actually somewhat protect them from the effects of hyperoxia,” says Dr. Tipple, whose recent research has appeared in the American Journal of Physiology—Lung, Cellular and Molecular Physiology; the American Journal of Physiology—Regulatory, Integrative and Comparative Physiology; Free Radical Biology and Medicine; and Antioxidants and Redox Signaling. He is most excited about the potential to develop clinical therapies to help babies’ lung cells protect themselves. “Ideally, we’d like to develop treatments that could be used prior to the baby being born, much like what is done with corticosteroids given to the pregnant woman.”
Dr. Tipple and his colleagues hope to study this system and its therapeutic potential further with the support of future grants. Their laboratory work also explores the role of thioredoxin-1 in the creation of pathologic cells that develop during pulmonary hypertensive diseases and the role of COX-2 in newborn hyperoxic lung injuries and inflammation. This variety allows them to form a more complete picture of lung tissue formation and damage when subjected to adverse conditions.
“My clinical training gives me a way to think about the things we’re doing at the bench in a way that makes me uniquely positioned to understand what we know and what we don’t know,” says Dr. Tipple, who also is medical director of the NICU at Mt. Carmel East Hospital. “We want the findings we’re making at a basic level to have the ability to be translated to care at the bedside.”
In addition, he and his research team would like to explore the potential that any therapies they develop for lung protection from hyperoxia could extend to other organs. “You’re taking an incompletely developed human being and asking them to develop normally in an environment that’s completely different than that in utero,” he says. “Oxidative stress isn’t really isolated to the lungs—the effects of hyperoxia are certainly systemic, and the big picture is that this sort of translational therapeutic approach could have effects on more than just the lungs.”
Chen B, Nelin VE, Locy ML, Jin Y, Tipple TE. Thioredoxin-1 Mediates Hypoxia-Induced Pulmonary Artery Smooth Muscle Cell Proliferation. American Journal of Physiology—Lung, Cellular and Molecular Physiology. 2013 Sep, 305(5):389-95.
Britt RD Jr, Velten M, Tipple TE, Nelin LD, Rogers LK. Cyclooxygenase-2 in Newborn Hyperoxic Lung Injury. Free Radical Biology and Medicine. 2013 Apr 25, 61C:502-511. [Epub ahead of print]
Velten M, Britt RD Jr, Heyob KM, Welty SE, Eiberger B, Tipple TE, Rogers LK. Prenatal Inflammation Exacerbates Hyperoxia-Induced Functional and Structural Changes in Adult Mice. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology. 2012 Aug 1, 303(3):279-90.
Locy ML, Rogers LK, Prigge JR, Schmidt EE, Arnér ES, Tipple TE. Thioredoxin Reductase Inhibition Elicits Nrf2-Mediated Responses in Clara Cells: Implications for Oxidant-Induced Lung Injury. Antioxidants and Redox Signaling. 2012 Nov 15, 17(10):1407-16.