Grant: Project Grant

After a baby is born, air rushes into the lungs with its first breath - but to pick up oxygen from that breath, blood urgently has to flow to the lungs too. Newborn lung blood flow is normally triggered by the presence of oxygen. Babies who have difficult deliveries, or who don't get enough oxygen during their birth, sometimes can't get enough blood flowing to their lungs. So even when they try to breathe, they can't pick up oxygen from the inhaled air - and they stay blue. This disease is called newborn pulmonary hypertension. It accounts for 10% of admissions to the newborn ICU, and these blue babies are the sickest in the newborn ICU. We have some drugs to treat them, but they don't always work. There is a rush to make new, better drugs. Lung blood vessels need to relax to let blood flow, using a system of signals inside the cell called the adenylyl cyclase pathway. We studied effects of low oxygen levels on the muscle lining the blood vessels of the newborn lung. We found that exposure to low oxygen makes the adenylyl cyclase enzyme slow down, like a foot on the brake of a car. This is because the reactive nitrogen species made in low oxygen stick to a critical part of this enzyme, triggering its off switch. That means lung blood vessels can't relax, and blood won't flow into the baby's lungs. Even after oxygen levels normalize, this enzyme doesn't resume its normal function. There are new drugs on the market which propose to treat pulmonary hypertension by increasing reactive nitrogen species. We are scared that they could trigger adenylyl cyclase's off switch, making pulmonary hypertension worse instead of better. Using well-tested animal and cell models of pulmonary hypertension, we plan to map the reactive oxygen and nitrogen species made in lung blood vessels during low oxygen, to find out what precise combination triggers adenylyl cyclase's off switch and how that happens. This will help identify safer drug targets to treat babies with this lethal disease.