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Drug Under Study Appears Able to Restore Premature Lung Function

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Duke Health News 919-660-1306

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."

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