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Chronic Lung Disease Affecting Premature Infants
"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 occurence rate of this disease," says Jesse Roberts Jr., MD, of the MGH departments of Anesthesia and Pediatrics and the Cardiovascular Research Center, the papers 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 treatment mandatory 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 commonly chronic, requiring long-term therapy 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.
Prior 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 therapy 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 linked to 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 therapys safety needs to be reviewed before we can plan a clinical trial, but its quite possible that this treatment 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.
Posted by: Emily Source