Some 20 to 40 percent of extremely premature infants suffer abnormal lung development leading to bronchopulmonary dysplasia, a chronic lung disease that can cause long-term breathing problems.
Little is known about how to predict whether a premature infant will develop BPD in the weeks after birth, much less how to prevent or treat it. Now, gene-chip studies of these tiny babies' umbilical cords provide unexpected, much-needed leads into predicting and treating this debilitating condition.
The study – one of the first uses of gene-chip (microarray) analysis to study diseases of premature newborns – was led by Isaac Kohane, MD, PhD, director of the Children's Hospital Informatics Program (CHIP), based at Children's Hospital Boston and affiliated with Harvard Medical School and the Harvard-MIT Division of Health Sciences and Technology, and Jennifer Cohen, MD, a neonatology fellow at Children's. Findings will appear online in Genome Biology (http://genomebiology.com) on October 4.
Kohane, Cohen and colleagues obtained samples from the umbilical cords of 54 surviving infants born at less than 28 weeks' gestation and analyzed the activity of all 30,000-odd genes for each infant. The specimens were collected as part of the Extremely Low Gestational Age Newborn (ELGAN) study (www.elganstudy.org/), a national study of infants born more than three months early. Twenty of the 54 infants developed BPD after birth; the other 34 did not.
“In the infants who went on to have BPD, we were surprised and intrigued to find a difference in a biochemical pathway that's also disrupted in adult chronic obstructive pulmonary disease (COPD),” says Kohane, the study's senior author.
The pathway, known as the chromatin remodeling pathway, is responsible for the “unwrapping” of coiled strands of DNA, which must occur before a gene can act or be “expressed.” When it is disrupted, certain genes for inflammatory proteins get stuck “on,”and the inflammation makes lung tissue degenerate and scar, Kohane explains. (Although the lungs are uniquely vulnerable, he speculates that other tissues in the newborn are also affected.)
The pathway has also been shown to be involved in COPD, the collective term for chronic bronchitis and emphysema, which obstruct airflow and make breathing difficult. A group of drugs known as histone deacetylase inhibitors are directed at this pathway, and are being developed as a treatment for COPD(1). Kohane speculates that they might also prevent or treat BPD.
“If you can prevent that pathway from being switched on and chewing away the lung, you might prevent BPD and perhaps improve the rocky clinical course of premature newborns,” he says.
In addition, interrupting this inflammatory process might not only slow or halt infants' progression to BPD directly, but could also avoid the need for them to be on the ventilator for prolonged periods, notes Cohen, the study's first author. Very premature infants usually require mechanical ventilation to stay alive – yet this life-saving measure ironically contributes to the development of BPD.