Archive for July 2nd, 2017

Could factors that prevent the formation of new blood vessels in the lungs account for the high prevalence of pulmonary disease in infants with down syndrome? The answer could have far-reaching implications that extend beyond lung health.

Conditions such as underdeveloped lungs, known as pulmonary hypoplasia, and high blood pressure in the arteries of the lungs, known as pulmonary arterial hypertension (PAH), occur in approximately 20 percent of children born with Down syndrome, according to data collected by Csaba Galambos, M.D., Ph.D., a pediatric pathologist in the Children’s Hospital Colorado Department of Pathology and Laboratory Medicine and Associate Professor of Pathology at the University of Colorado School of Medicine.

A group of researchers led by Dr. Galambos is exploring, for the first time, why individuals with Down syndrome are more susceptible to these conditions. His lab has hypothesized that central to the development of pulmonar y hypoplasia and PAH is the suppression of the process that prompts the growth of new blood vessels, a chain of events called angiogenesis. Their discoveries could lead not only to therapies for pulmonary disease in individuals with Down syndrome, but also to treatments that may improve lung development and function in all patients.

A DOUBLE-EDGED SWORD

Dr. Galambos’ fascination with angiogenesis began y ears ago, he read a paper by late angiogenesis r esearcher Judah Folkman, M.D., of Harvard University. Dr. Folkman’s research showed that solid tumors depend on newly formed blood vessels for their growth. Overexpression of chemical signals that block the process — known as angiogenesis inhibitors — may occur in people with Down syndrome. According to Dr. Galambos, that protective property may come with a downside in the form of pulmonary underdevelopment and dysfunction.

“Chromosome 21 has many genes that act as anti-vascular or antiangiogenic factors,” he said. “In people with Down syndrome, there is an excess of anti-angiogenic factors that could significantly block normal vessel development in all organs, including the lungs. Our goal is to explore a previously unrecognized role of the chromosome 21-specific anti-angiogenic factors that may lead to lung immaturity and increase the risk for severe PAH in infants and children with Down syndrome.”

MODELING ANGIOGENESIS

Using banked lung tissue samples, Dr. Galambos and colleagues created a number of different models to re-create angiogenesis and observe the effects of its impairment.

“We measured the messenger RNA expression levels of 84 angiogenesisrelated genes in Down syndrome fetal lung samples and typical controls, and we also looked at microscopic signs of impaired lung vascular growth,” Dr. Galambos said. “Not only did we discover that three potent chromosome 21-related anti-angiogenic factors are overexpressed significantly in the lung in utero, we also identified two other potent anti-angiogenic factors with significant overexpression that were unrelated to chromosome 21. Significantly, our analysis showed features of impaired vascular growth in these lungs.”

The next step for Dr. Galambos and his group was to develop cell-culture and animal models in which they could further test the effects of anti-angiogenesis.

“There are Down syndrome mouse models that carry three copies of portions of chromosome 21,” Dr. Galambos said. “We are excited that we are able to show, for the first time, that one of these models develops features characteristic of impaired lung development seen in the lungs of humans with Down syndrome.”

Dr. Galambos plans to use the mouse model to fur ther investigate the unique ways that Down syndrome affects angiogenesis, as well as the anti-angiogenic pathways that may play a role in abnormal pulmonary development and function. A 2017 C rnic Institute Grand Challenge Grant underwritten by the Global Down Syndrome Foundation will support his work. Dr. Galambos believes this research could produce findings — and point the w ay to novel therapies — that are applicable not only to patients with Down syndrome, but also to individuals in the gener al population with pulmonary hypoplasia and PAH.

THE NEXT FRONTIER?

Even as he explores the role of angiogenic impairment in lung disease, Dr. Galambos is pondering the possibility that it could also affect cognition in individuals with Down syndrome.

“It is well known that proper angiogenic signals are required for optimal nerve growth, supporting intellectual development,” he said.

“In Down syndrome and Alzheimer’s disease, nerve development and function are compromised. It has been shown that the thre edimensional vascular network of the brain is impaired in Alzheimer’s disease. It’s a realistic possibility that impaired angiogenesis not only causes underdeveloped lungs and PAH, but may also affect the development and function of neural networks of the brain in people with Down syndrome.”

Dr. Galambos believes a future in which clinicians use angiogenic therapies to treat lung disease and improve cognitive function in people with Down syndrome is possible — and he is doing his part to accelerate its arrival. 

NEW INSIGHT INTO NEONATAL HYPOXEMIA

Infants born with lung disorders who do not respond to advanced respiratory therapies usually have low blood oxygen content, or hypoxemia, according to Csaba Galambos, M.D., Ph.D., a pediatric pathologist in the Children’s Hospital Colorado Department of Pathology and Laboratory Medicine and Associate Professor of Pathology at the University of Colorado School of Medicine.

Dr. Galambos and his colleagues recently identified a group of blood vessels in infants with hypoxemia, including those with Down syndrome, that permit nonoxygenated blood to enter the lungs, therefore contributing to potentially life threatening hypoxemia. Now, they want to learn how these vessels function.

“Our next step is to design animal models that can help identify the regulating mechanisms that open and close these vessels in lung disease, including pulmonary arterial hypertension (PAH),” Dr. Galambos said. “These data will allow us to test interventions that aim to close the vessels, and that will lead to better oxygenation, less severe lung disease, and improved survival of infants with lung disorders, including PAH.”

Csaba Galambos, M.D., Ph.D., a pediatric pathologist in the Children’s Hospital Colorado Department of Pathology and Laboratory Medicine and Associate Professor of Pathology at the University of Colorado School of Medicine, has received many notable grants to further his research into the links between lung disease and Down syndrome, including:

2014–2016 Jérôme Lejeune Foundation Grant, $39,000 “Role of Impaired Angiogenesis in the Pathogenesis of Severe Cardiopulmonary Disease in Children with Down Syndrome”

Role: Principal Investigator
2017 Crnic Grand Challenge Grant, $50,000 “Overexpression of Anti-angiogenic Genes Impairs Lung Development in Dp16 Mice”

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