Erk3 responsible for success of steroids in treating newborn lungs
By Ruth SoRelle, M.P.H.
It's no secret that giving steroids to pregnant women facing premature birth can hasten the development of their infants' lungs. However, no one knew why this treatment works.
Now, Dr. Kjersti Aagaard-Tillery, assistant professor of obstetrics and gynecology at Baylor College of Medicine, and her colleagues have found that a gene called Erk3 is at the bottom of the mystery. A report on their works appears in a recent issue of the Proceedings of the National Academy of Sciences.
Problem in mice
"When we generated newborn mice lacking the gene for Erk3 (extracellular signal-related kinase 3), they were growth-restricted and died of acute respiratory failure within the first 24 hours of life," said Aagaard-Tillery, a senior author of the report. "When we completed our microscopic and histological studies, it appeared that the lung architecture had developed normally with the correct number of lobes but the saccular structures (or 'air sacs') were immature and underdeveloped."
She said further analyses led the research team to conclude that the cells responsible for final functional maturation (type II pneumocytes) had not developed normally and contained more glycogen than normal animals. The glycogen replaces surfactant, a substance essential for normal breathing.
"It looked akin to what we see in growth-restricted and premature human infants," Aagaard-Tillery said.
When compared to babies who are not growth-restricted but born at the same gestation, these infants fare poorly, she said.
Human treatment for mice
When she and her colleagues from Canada sought to treat the mice, they turned to the steroids commonly used in treating mothers anticipating premature birth or growth restricted babies.
"We found we could correct the lung defect in terms of the cellular anatomy," she said. "After the steroids, we could see no evidence of delayed lung maturation and the glycogen content in the type II pneumoctyes normalized. In other words, giving the mice steroids in the pregnancy overcame the genetic defect in their babies' lungs. It's the first time we have shown that we can correct the phenotypic (visible symptoms) result of a gene deletion by administering a maternal drug in its commonly used clinical form."
However, while the lung cells appeared mature, the infant mice still lacked the drive to breathe and died, although later than would have happened without treatment. This was again similar to the clinical situation in humans, where premature babies from mothers given a single course of steroids before 34 weeks of pregnancy fare better.
Erk3 holds more answers
"Our current efforts in the laboratory are focused on finding out precisely which molecular pathways in the lung are affected by the steroids and how it is that we can restore normal lung development but the neonates will still experience respiratory failure," she said.
She also wants to find out where Erk3 fits in determining fetal growth and how that meshes with the effect of a protein called insulin-like growth factor 2 in determining a newborns size.
"This shows us the beginnings of the science behind what we have done clinically for over a decade," said Aagaard-Tillery. "Ultimately, these mice provide us with the tools to figure out why giving the pregnant mothers steroids will benefit their premature and growth-restricted babies. Continuing this work will give us more clues that we can use to further improve outcomes for these babies."
Others who took part in this work include Sonia Klinger, Benjamin Turgeon, Kim Lévesque and Sylvain Meloche of the University of Montreal in Montreal, Quebec, Canada, and Geoffrey A. Wood of the University of Guelph in Guelph, Ontario, Canada.
Funding for this work came from the Canadian Institutes for Health Research and the NIH Directors New Innovator Award.
