Researchers Tap Into Body’s Natural Antioxidant System to Protect Lungs of Premature Infants

Newswise — Columbus, Ohio. Imagine lungs so fragile that a breath of regular room air could result in a lifetime of breathing difficulties, or even death. Each year, as many as 10,000 premature babies face that exact scenario, when the necessary treatments they receive also cause damage to lung tissue, leading to a chronic disease called bronchopulmonary dysplasia (BPD). BPD mostly affects premature infants who are born more than ten weeks before their due date, weigh less than two pounds and have breathing problems that require oxygen therapy. “Babies lungs aren’t physiologically ready for room air until they are at least 35 weeks old. We give pre-term infants medicines along with supplemental oxygen that allows them to breathe, and these interventions have saved hundreds of thousands of lives,” said Trent Tipple, MD who is BPD researcher in the Center for Perinatal Research at Nationwide Children’s Hospital (NCH). “But the interventions come with a cost. Infant’s lungs are forced to process oxygen weeks before they develop the ability to do so and weeks before natural protective antioxidant responses are in place.”

Now, after almost a decade of research, neonatal experts like Tipple think they have discovered the secret to reducing BPD’s impact by using an existing arthritis drug to trigger the natural antioxidant defense system in the lungs.

It’s a translational medicine breakthrough that’s been made possible through years of investigation by Tipple, who during his pediatric residency wondered why the lungs of premature babies stopped growing once they were born.

“We know ventilators cause physical damage to lung tissue, but that wasn’t totally explaining why these babies’ lungs just stopped developing.” said Tipple, who is also an assistant professor of pediatrics at The Ohio State University College of Medicine. “I decided to study what was happening on a molecular level when cells that are supposed to be in a low oxygen environment are suddenly exposed to higher levels of oxygen.”

Since then, with support from the National Blood, Lung, and Heart Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Ohio State University Center for Clinical and Translational Science (CCTS), Tipple’s research team and partners have been able to conduct multiple studies looking at BPD mechanisms.

Answers from cancer tumors and rheumatoid arthritis?In 2006, Tipple who was working with Dr. Lynette Rogers (NCH), Dr. Charles V. “Skip” Smith (Seattle Children’s Research Institute) and Dr. Steve Welty (Texas Children’s Hospital) and noted that numerous cancer studies showed tumor cells thrived in a low oxygen environment, but in a hyperoxic, or high oxygen environment, tumor cells grew more slowly. Cancer researchers had attributed this process, in part, to a specific tumor growth pathway regulated by the protein thioredoxin (Trx).

Tipple’s team conducted several mouse studies revealing that neonatal lungs might also use the Trx system to regulate growth, and that the function of the protein is directly related to changes in oxygen levels, transmitting signals to the genes that instruct them to stop lung development. Trx is typically thought of as an anti-oxidant that helps to remove damaging free-radicals in both adult and infant lungs. The team showed that adult mice treated with a inhibitor of the Trx system, called aurothioglucose (ATG), had less lung injury when exposed to high oxygen levels. ATG has been used for decades as a rheumatoid arthritis treatment.

Then pivotal experiments using a compound closely related to ATG, auranofin (AFN), in mouse lung cells, published in November 2012, clarified that it was actually another process downstream from the Trx system that provided the protection against oxygen-induced injury. In the presence of AFN, activation of a protein called Nrf2 kick-starts antioxidant defenses, reducing damage to lung cells in a hyperoxic environment. Additional studies suggest that ATG uses activation of Nrf2 to provide protection against oxygen-induced injury by this same pathway. These findings may be useful for both newborn and adult patients that require oxygen therapy.

“Currently we are researching the optimal dose of ATG in a BPD mouse model, looking at how Nrf2 is activated and seeing if we can reduce the severity of oxygen-induced lung injury,” says Tipple. “Our preliminary findings are very promising. We’re also investigating ATG’s potential to protect other organs like the brain that are negatively impacted by oxygen therapy.”

Adult lung disease holds clues to BPDIn 2011, working with researchers Drs. Clay Marsh and Melissa Piper at the Ohio State University, Tipple received a pilot award from the CCTS to study microRNA-17~92 expression in BPD. miR-17~92 is a family of molecules that controls genetic expression and has been implicated in a variety of diseases. Drs. Marsh and Piper are studying its role in idiopathic pulmonary fibrosis, a disease where lung tissue becomes inexplicably scarred.

Tipple is currently using a biospecimen repository of neonatal lung tissue maintained by Dr. Gloria Pryhuber at the University of Rochester to determine if miR-17~92 may offer a therapeutic target to prevent BPD. Preliminary results indicate that preterm infants who died with BPD had lower miR-17~92 expression, which may correlate with the severity of their lung injury. This finding could help lead to a targeted therapy to increase miR-17~92 in the lungs of premature neonates to help reduce the development of BPD.

“The CCTS support has been critical not just from a financial perspective, but I’ve had access to great mentors in Ohio State’s Dr. Chandan Sen and Dr. Marsh. Their leadership and knowledge is something I’ve been able to pass on my former mentee, Morgan Locy, who has worked on many of these BPD studies,” noted Dr. Tipple.

Locy is now an MD/PhD student at University of Alabama-Birmingham, and Tipple would like to think that Locy’s experiences in his lab at NCH has helped establish a solid foundation for his career.

“I’ll never forget Dr. Welty telling me that I could either help one baby at a time, or do something that could impact many,” said Tipple. “I’ve had excellent mentors and collaborators that are allowing me to fulfill that goal.”

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About The Ohio State University Center for Clinical and Translational ScienceDedicated to turning the scientific discoveries of today into the life-changing health innovations of tomorrow, The Ohio State University Center for Clinical and Translational Science (CCTS) is a collaboration of experts including scientists and clinicians from six Ohio State Health Science Colleges, Ohio State’s Wexner Medical Center and College of Medicine, and Nationwide Children’s Hospital. Funded by a multi-year Clinical and Translational Science Award (CTSA) from the National Institutes of Health, OSU CCTS provides financial, organizational and educational support to biomedical researchers as well as opportunities for community members to participate in credible and valuable research. The CCTS is led by Rebecca Jackson, M.D., Director of the CCTS and associate dean of research at Ohio State. For more information, visit http://ccts.osu.edu.

About Nationwide Children’s HospitalRanked in all 10 specialties on U.S.News & World Report’s 2013-14 “America’s Best Children’s Hospitals” list and among the Top 10 on Parents magazine’s 2013 “Best Children’s Hospitals” list, Nationwide Children’s Hospital is one of the nation’s largest not-for-profit freestanding pediatric healthcare networks providing care for infants, children and adolescents as well as adult patients with congenital disease. As home to the Department of Pediatrics of The Ohio State University College of Medicine, Nationwide Children’s faculty train the next generation of pediatricians, scientists and pediatric specialists. The Research Institute at Nationwide Children’s Hospital is one of the Top 10 National Institutes of Health-funded free-standing pediatric research facilities in the U.S., supporting basic, clinical, translational and health services research at Nationwide Children’s. The Research Institute encompasses three research facilities totaling 525,000 square feet dedicated to research. More information is available at NationwideChildrens.org/Research.

The Ohio State University Center for Clinical and Translational Science (CCTS) is funded by the National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program. Research reported in this release was supported by the National Center For Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000090. The content of this release is solely the responsibility of the CCTS and does not necessarily represent the official views of the NIH.