Leveling the field for babies with persistent pulmonary hypertension
If he can figure out which babies will be born unable to breathe properly, Dr. Stephen M. Black thinks he can help change that.
"When these kids are born, you have a short amount of time to intervene or you get brain damage," says Dr. Black, cell and molecular physiologist at the Medical College of Georgia Vascular Biology Center.
Unfortunately, persistent pulmonary hypertension comes as a surprise in full-term babies, says Dr. Jatinder J.S. Bhatia, chief of the MCG Section of Neonatology. The pregnancy seems uneventful until the hours following birth when breathing trouble requires rapid transport to a neonatal intensive care unit.
"What happens in utero is that all your gas exchange is through the placenta, so there is only about 8 percent of cardiac output actually going through the lungs," says Dr. Black. "When you are born, obviously there is 100 cardiac output and you need to breathe."
When babies can't breathe well, physicians quickly determine whether the primary problem is the heart or lungs, Dr. Bhatia says. When it's the lungs, babies first get oxygen therapy and possibly mechanical ventilation. If it is pulmonary hypertension, the powerful vasodilator, nitric oxide, is used to reduce high pressures in the pulmonary circuit and allow the transition to a normal circulation. Neonatologists also have begun using the popular erectile dysfunction drug, Viagra, to dilate tiny pulmonary vessels.
If these therapies fail, they turn to the more invasive extracorporeal membrane oxygenation, which resembles heart-lung bypass used during heart surgery. This approach is most helpful for newborns with conditions such as pulmonary hypertension as well as aspirating waste products in utero, congenital heart disease and congenital diaphragmatic hernia.
Dr. Black's focus is the babies whose vessels have become thick-walled, inflexible pipes that cannot transition to an elastic state. Flexibility enables adequate blood to get into the lungs so it can be replenished with oxygen then head back to the heart which pumps it out to the body.
"If you can keep the kids alive for four or five days, the blood vessels remodel back to what they should be," says Dr. Black, who joined the MCG faculty in March. He wants vessels ready for their job at birth
He's studying how factors that regulate blood vessel expansion go awry in the two to six babies per 1,000 with persistent pulmonary hypertension and finding many cards stacked again them.
"Basically the whole pathway is shot," he says. "The main vasodilator in the lungs is nitric oxide and the main vasoconstrictor is endothelin. They have to be in very good balance. What happens in our animal model – and there is evidence that it happens in kids who die from this – is that nitric oxide synthase, the enzyme that makes nitric oxide, decreases in utero and endothelin levels increase. When you lose the vasodilator and you gain proliferative response, essentially the muscle cells just get bigger. The end result is these kids can die as soon as they are born."
He and Dr. Jeffrey Fineman, a whole animal physiologist and physician at the University of California, San Francisco, are using sheep as a surgical model for this condition.
They have found one way endothelin enlarges smooth muscle cells on exterior blood vessel walls is by activating an enzyme that makes free radicals, which are reactive, unpaired electrons that work as signaling molecules.
Free radicals are fine, even necessary, as long as they are available in the proper numbers. But at least one of these radicals, hydrogen peroxide, escapes from smooth muscle cells into endothelial cells, which line blood vessels where, in a double-whammy to flexibility, it inhibits the expression and the activity of nitric oxide synthase.
"A whole host of enzymes are involved in vasodilation and a host of enzymes are involved in vasoconstriction. What happens in these children is all the vasoconstrictors go up and the vasodilators go down," says Dr. Black. "We think hydrogen peroxide is a key molecule in there."
In this unfortunate scenario, even nitric oxide malfunctions.
Nitric oxide dilates vessels by activating a protein that stimulates production of cyclic GMP. At low levels, hydrogen peroxide activates the protein that enables production of cyclic GMP, enabling a chain reaction that results in calcium being pumped out of smooth muscle cells and blood vessels relaxing. Endothelin does just the opposite.
"We have found that if you chronically give the cells hydrogen peroxide, it down regulates those enzymes. So your nitric oxide generation is decreased and the ability to activate cyclic GMP has gone away as well," says Dr. Black.
As if that weren't bad enough, levels of phosphodiesterase, an enzyme that degrades cyclic GMP, rise, Dr. Black suspects because of the increase in oxidative stress. This phosphodiesterase increase is the reason Viagra, a phosphodiesterase inhibitor, is used for these babies.
Now that they better understand the complex scenario, Dr. Black and his colleagues want to look at the plasma of mothers and babies with persistent pulmonary hypertension for biomarkers that predict a baby is headed for trouble.
They also are looking at therapies, probably antioxidant therapy delivered right to cells, to stop signals from free radicals that result in bulky, dysfunctional pulmonary blood vessels at birth. "The driving force in these babies is the free radicals that make the muscles grow," says Dr. Black.
Dr. Black's other primary research interest is perinatal stroke, in which nitric oxide synthase also appears a key player and a bad one. "Nitric oxide gets activated in stroke and kills neurons," he says. He and colleague Dr. Donna Ferriero, pediatric neurologist at the University of California, San Francisco, have developed a culture model to study what happens to the hippocampus when it's deprived of critical oxygen and glucose. They are dissecting the no-doubt, complex chain of signaling that leads to neuronal death in babies and looking for viral delivery systems that can help protect brain cells.
Dr. Black is principal investigator on four National Institutes of Health grants, an American Heart Association-Pacific Mountain Affiliates grant and a grant from Foundation Leducq, a French foundation supporting international efforts to combat cardiovascular disease. He recently was appointed to the National Heart, Lung and Blood Institute's Board of Scientific Councilors and NHLBI's Program Project Review Committee. Dr. Black came to MCG from the University of Montana and previously worked at the University of California, San Francisco, and Northwestern University.
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