October 23, 1998

Investigator seeks clues to premature infant blindness

Investigator seeks clues to premature infant blindness

Researchers at Vanderbilt University Medical Center will be gaining a better understanding in the laboratory about retinopathy of prematurity (ROP), a form of blindness that strikes some premature infants who are given high doses of oxygen because their lungs aren¹t fully developed.

Dr. John Penn has joined the Department of Ophthalmology and Visual Sciences as a professor and will spend most of his time delving into the cellular and molecular events that precede the development of ROP.

ROP, first identified in 1942, occurs in about 3,500 premature infants each year in the United States. Estimates are that between 350 and 500 infants each year are blinded because of the condition. The remaining infants can suffer some long-lasting visual problems.

The problem occurs when an infant is given supplemental oxygen at birth to aid his or her underdeveloped lungs. At that time, the blood vessels in the child¹s retinas are still developing, and oxygen therapy can cause these blood vessels to grow abnormally. After the abnormal growth begins, vessels that are supposed to remain with the retina of the eye can actually grow into the center of the eye, causing retinal detachment. The only way to repair the problem is with invasive laser therapy, which can cause damage to healthy retinal tissue.

Much of Penn¹s work is investigating ways to stop the abnormal growth before it begins.

At the Arkansas Center for Eye Research in Little Rock, where Penn spent a decade conducting numerous studies, he developed an animal model that helps researchers understand what is happening in the retina when the blood vessels aren¹t growing as they should. In Penn¹s model, rats are kept in premature infant incubators and exposed to oxygen in a way that they develop this abnormal growth. Then, they are given drugs to try to stop it.

"The maturity of the retina, particularly blood vessels in the retina, is tied to the time when animals open their eyes," Penn said. "It¹s true for all animals," he said. "Development of an infant¹s blood vessels is timed so they finish the process right at birth. Animals open their eyes postnatally, so you can study the process of retinal blood vessel development and change it around with oxygen exposure after they¹re born. It¹s a lot easier to study the process. That window of time that¹s important in infants late in gestation is displaced to a postnatal time in many animals."

Penn¹s basic research is divided into three areas:

o Angiogenesis, the abnormal growth of retinal blood vessels in the retina. In the eye a factor called vascular endothelial growth factor (VEGF) is produced and binds to receptors on the surface of capillaries and stimulates these cells to perform various functions that collectively constitute angiogenesis. Penn¹s research will take a closer look at the cell signal pathways by which these functions are initiated.

o Cell migration. When angiogenesis occurs, the endothelial cells (the cells the make up the walls of the blood vessels) must attach to the surrounding extracellular matrix and migrate. Penn's research will look for attachment mechanisms.

o The metastatic aspect of angiogenesis. The endothelial cells produce enzymes that chew up the matrix in advance of their progressive proliferation in kind of a pac-man fashion. The research will look at the enzymes and test potential inhibitors.

Penn¹s clinical research focuses on how the variability of oxygen in the bloodstream during oxygen therapy causes ROP. Penn¹s research in Arkansas showed that children with the most variable blood gas profiles developed the most severe forms of ROP. Looking at modifying the ways oxygen is delivered may hold the answer.

Early researchers believed that infants who received more oxygen had worse incidences of ROP. But Penn¹s research has shown the importance of oxygen variability in the process.

Penn is now designing an oxygen delivery system that can automatically alter the percentage of oxygen delivered to an infant as the infant's demands change.

"It may be possible to develop a delivery system that will calibrate the bloodstream oxygen level more precisely," he said. "The efforts of our neonatologists are heroic. They can¹t work harder or be any more conscientious in the NICU, but the technology can be improved."