While other genes have been identified as having roles in lung development, this master gene, called Foxa2, controls key factors that allow the lungs of a fetus to develop fully and eventually breathe air. While Foxa2 was previously known to exist, its role in lung maturation and function at birth were not known.
When Foxa2 is missing in newborn mice, respiratory distress syndrome and in many cases, death, was almost certain to follow, said Jeffrey A. Whitsett, MD, chief of Neonatology, Perinatal and Pulmonary Biology at Cincinnati Children's and senior author of the study that appears in the October 5 issue of the Proceedings of the National Academy of Sciences (PNAS).
"It was surprising to us that a single gene was able to orchestrate so many other aspects of lung function we know are critical for survival at the time of birth. The discovery of this gene and understanding of how it works could lead to new treatments for premature infants and for children and adults who suffer from lung disease or injury," he said.
Because lungs do not fully mature until the last trimester of gestation, when an infant is born prematurely, the lungs are not fully developed and lack the necessary amount of surfactant needed to keep the lungs working properly. Surfactant is a natural chemical found in the lungs that prevents alveoli - the tiny airways in the lungs - from collapsing and in turn allows the lungs to open when the newborn starts to breath. The absence of surfactant causes respiratory distress syndrome within hours of birth.
"We showed that Foxa2 regulates a group of genes that stabilize surfactant production, which is required for the transition from the womb to breathing air and to protect the lungs from disease, bacterial infection and other disease and injury," Dr. Whitsett said.
Foxa2 has an important role in the development of surfactant. It resides in the respiratory epithelial cells, which combines surfactant proteins and lipids (essential fat), which in turn produces surfactant.
Researchers bred mice with and without the Foxa2 gene. When the gene was deleted, the knockout mice developed all the signs and symptoms of respiratory distress syndrome on the first day of life and died within hours of birth. The few knockout mice that did survive, developed asthma-like symptoms and emphysema later in life. On the other hand, when Foxa2 was fully intact, the newborn mice survived normally.
Foxa2 is different from other genes because it is a master gene: it controls how other genes work. For example, in the knockout mice, genes expressed in surfactant proteins and genes involved in lipid metabolism, were directly influenced by the absence of Foxa2.
Researchers found that when the Foxa2 gene was deleted, the Foxa1 gene was expressed more strongly, perhaps in an effort to compensate for the absence of the parent gene, Dr. Whitsett said. Still, the Foxa1 was not strong enough to support the development of sustainable healthy lungs in the mice.
According to the March of Dimes, one in eight infants in the U.S. are born prematurely. Furthermore, approximately 24 percent of all infants born prematurely will die in the first month of life and in most cases, it is as a result of respiratory distress syndrome.
Steroids have become one of the most common courses of treatment for infants with underdeveloped lungs. Steroids work by stimulating lung development, but their use has been associated with side effects, such as cerebral palsy, asthma and bronchitis.
The identification of Foxa2's role in lung development is expected to lead to new treatments for premature babies, children and adults with lung disease or lung injury.
The study was funded by the National Heart, Lung and Blood Institute of the National Institutes of Health.
Study collaborators include researchers from the University of Pennsylvania, Vanderbilt University and the National Institute for Medical Research in London.
Cincinnati Children's Hospital Medical Center is a 423-bed institution devoted to bringing the world the joy of healthier kids. Cincinnati Children's is dedicated to transforming the way health care is delivered by providing care that is timely, efficient, effective, patient-centered, equitable and safe. It ranks third nationally among all pediatric centers in research grants from the National Institutes of Health. The Cincinnati Children's vision is to be the leader in improving child health. Additional information can be found at www.cincinnatichildrens.org.
Journal
Proceedings of the National Academy of Sciences