DURHAM, N.C. – Doctors at Duke University Medical Center have shown how to prevent severe lung injury in newborn animals without subjecting them to the potential brain-damaging side effects of steroids.
The new antibody treatment has been tested in rats to date but is designed to work in premature babies, according to a study published in the August issue of American Journal of Physiology. Researchers hope to begin using the treatment in humans within the next two years, pending further testing, said Dr. Richard Auten, assistant professor of pediatrics at Duke and the lead author of the study.
"Chronic lung disease in premature babies is the single most important factor in predicting which of these babies will have learning disabilities and asthma later in childhood, so treating lung disease in these babies is of critical importance," said Auten, a specialist in treating critically ill newborns.
Premature babies are born with immature lungs that lack three vital elements: a substance called surfactant, a sufficient number of alveoli (air sacs) and an enzyme that transforms reactive oxygen molecules into byproducts that can be discarded as waste. All of these factors prevent the lungs from adequately breathing and processing oxygen. Ventilators help these babies breathe, but they sometimes unavoidably stretch and further injure lung tissue.
To repair these multiple injuries, the lungs call in white blood cells. Yet these cells inadvertently stay too long in premature lungs and end up creating damage of their own, Auten explained.
"A baby's lungs attempt to repair injury by calling in white blood cells, which heal damaged tissue and fight off foreign invaders," Auten said. "But this call to arms in premature babies is slow to get started and just as slow to stop. Once the white blood cells are there, they continue to fight long after there is an enemy to conquer. The result is they end up fighting the very tissue in the lungs that they came to protect."
Doctors traditionally use steroids to slow recruitment of white blood cells in response to lung injury. But steroids are not specific, and they inadvertently slow tissue growth in other areas that are critical to the newborn's development. As a result, steroids often stunt lung cell and brain cell growth, and impair overall immune function in premature babies.
So Auten's team set out to find and test a new compound that had the benefits of steroids but without its risks. The National Institutes of Health and the American Lung Association supported their studies using an antibody called anti-CINC-1. The antibody prevents white blood cells from staying too long and waging a full-fledged war inside the body.
Steroids counteract this exaggerated inflammatory response by slowing the growth and recruitment of white blood cells and many other cells, as well. Anti-CINC-1 works in a much more targeted manner than steroids do, said Auten. It impairs only the action of a particular type of white blood cell called a neutrophil -- the most powerful at destroying foreign bacteria and, when no bacteria are present, healthy tissue in the lungs.
Specifically, anti-CINC-1 blocks the action of a cell messenger or "cytokine" called neutrophil chemokine CINC-1. This particular cytokine tells the neutrophil how to behave. Anti-CINC-1 acts as an antibody to this cytokine, essentially shutting off its signal pathway to the neutrophil, so that the message to go to the lungs is never received.
Without neutrophils present, there is much less inflammation-caused damage in the lungs, Auten said. "Inflammation is a good thing in proper doses, because it means that white blood cells are doing their job," said Auten. "But prolonged inflammation simply exacerbates the injury already present within the lungs. Shortening the duration of inflammation may be a key to restoring normal lung development in babies."
Auten said that giving the drug at the appropriate stage of treatment allows the necessary inflammatory response to begin, but curtails it when the inflammation may exceed its benefit.
The Duke team derived its results by administering 95 percent oxygen to the rats for eight days, in order to mimic the injury premature babies might receive during ordinary medical care, followed by two days of treatment with anti-CINC-1. After receiving the anti-CINC-1, the rats showed normal body weight, normal lung function and normal lung cell division, meaning their cells were continuing to grow and multiple normally. "This could open up a whole new treatment model for premature babies suffering from severe oxygen injury," said Auten. "It looks very promising."