Researchers from Massachusetts General Hospital, in collaboration with scientists from the Genzyme Corporation, have identified a potential treatment for a chronic lung disease affecting premature infants. In a study to appear in the American Journal of Physiology - Lung Cellular and Molecular Physiology, which has received early online release, the scientists find that the activity of transforming growth factor-beta (TGF-beta, a protein that controls many essential cellular functions) is elevated in the lungs of an animal model of bronchopulmonary dysplasia and that treatment with an antibody to TGF-beta both decreased the growth factor's activity and improved lung development.
"Our findings show for the first time that TGF-beta is a major player in causing bronchopulmonary dysplasia and that inhibiting its activity in the injured newborn lung may decrease the severity or incidence of this disease," says Jesse Roberts Jr., MD, of the MGH departments of Anesthesia and Pediatrics and the Cardiovascular Research Center, the paper's senior author. "Since bronchopulmonary dysplasia is the most significant lung disease of premature infants, these results are very exciting."
Bronchopulmonary dysplasia (BPD) affects about 15 percent of premature infants, resulting in chronic lung disease in 10,000 to 20,000 infants in the U.S. each year, and is often caused by the mechanical ventilation and oxygen therapy required for their survival. Since BPD is more common in the most premature infants -- affecting nearly 65 percent of those with a birth weight less than 1 pound, 10 ounces -- its incidence has increased as more of the tiniest infants are surviving. The lung damage produced by BPD is usually chronic, requiring long-term treatment and frequently affecting growth and neurological development. BPD is second only to asthma as the most costly disease of children in the U.S., and infants with BPD who survive can have lung disease into adulthood.
Previous studies have shown that TGF-beta helps regulate early fetal lung development, but its direct role in the maturation of pulmonary structures disrupted by BPD has not been known. Since research at other centers has suggested that elevated TGF-beta levels might interfere with later lung development, the MGH-led team investigated that possibility and its potential relationship to BPD. A group of pregnant mice received injections of either an antibody against TGF-beta or a control substance a few days before giving birth. Their offspring were housed in either normal air or 85 percent oxygen, a concentration known to cause BPD in mice, for 10 days after birth.
The newborn mice exposed to high oxygen levels without the neutralizing antibody treatment were found to have elevated TGF-beta activity in the peripheral regions of their lungs. Those mice also had incomplete development of the lung structures called alveoli and the tiny pulmonary blood vessels where gases are exchanged between the airway and the bloodstream, a deficit typically seen in BPD. The mice that also received the TGF-beta neutralizing antibody had significantly lower levels of growth factor activity and much more normal lung development.
Moreover, the improved lung development of the mice exposed to high levels of oxygen and treated with the neutralizing antibody was also associated with improved body growth. Those mice grew at a rate virtually identical to that of the animals that breathed normal air. Mice not treated with the antibody and exposed to elevated oxygen weighed 30 percent less than the air-breathing control group did at 10 days old.
"These findings need to be confirmed in other models of this disease, and the treatment's safety needs to be evaluated before we can plan a clinical trial, but it's quite possible that this therapy will help us treat these very sick babies," Roberts says. "It also is not far-fetched that TGF-beta-neutralizing therapies might have therapeutic potential in other human diseases. Studies are underway right now at our center and several others to evaluate that possibility." Roberts is an associate professor of Anaesthesia (Pediatrics) at Harvard Medical School and a neonatologist and pediatric anesthesiologist at the MassGeneral Hospital for Children.
The use of TGF-beta antibody to treat BPD was co-invented by Roberts and study co-author James Streisand, MD, an MGH anesthesiologist and clinical scientist at Genzyme Corporation; and the invention has been patented by the MGH and Genzyme. Additional co-authors of the study are first authors Hidekiko Nakanishi, MD, and Takahiro Sigiura, MD, PhD, of MGH Anesthesia and the CVRC, and Scott Lonning, PhD, of Genzyme.
The study was supported by a Genzyme -- Partners HealthCare Award for Translational Research.
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