Understanding the increase in pulmonary blood flow at birth

The transition to newborn life represents a major physiological challenge for the infant. The infant must clear its airways of liquid so that air can enter the lungs and pulmonary gas exchange can commence. This triggers a large increase in pulmonary blood flow (PBF), which is not only critical for underpinning the onset of pulmonary gas exchange, but is also vital for replacing umbilical venous return as the primary source of preload for the left ventricle. Despite its vital importance in the transition to newborn life, the factors regulating the increase in PBF at birth are still unclear. Recent X-ray imaging experiments have shown that, although lung aeration is the primary trigger, the increase in PBF at birth is not spatially related to ventilated lung regions. Instead, partial lung aeration causes a global increase in PBF, resulting in ventilation/perfusion mismatching in unventilated lung regions. This finding is contrary to the current understanding of the factors regulating the increase in PBF at birth and indicates that an unknown mechanism is involved. To investigate the factors regulating the increase in PBF at birth, a combined methodological approach will be used. State-of-the-art X-ray imaging techniques will be used in preterm rabbits to define the spatial relationships between lung aeration and PBF. Iodine will be injected into pulmonary vessels as a contrast agent to measure relative PBF and phase contrast X-ray imaging will be used to simultaneously indicate aerated lung regions. This technology was used to discover the spatial disconnection between ventilation and increased PBF at birth and it is only through its continued use that the mechanisms involved can be unravelled. However, as this imaging technique only provides information on PBF during iodine injections, it will be combined with a physiological approach in preterm lambs. While providing little information on V/Q matching in the lung, the sheep experiments will provide greater quantitative information on the temporal changes in PBF and its relationship with intravascular oxygen levels. In Aim 1 we will determine the relative roles of lung aeration and oxygen in the increase and regional distribution of PBF after birth. We hypothesise that increasing inspired oxygen content will enhance the increase in PBF in ventilated lung regions, but its absence will not prevent the increase in PBF in unventilated regions. In Aim 2, we will determine the relative role of vagal nerves in the increase in PBF at birth. We hypothesize that, during lung aeration, the movement of liquid from the airways into the interstitial tissue activates J- receptors, which mediate global vasodilation of pulmonary vessels. These experiments will provide valuable new insights into the mechanisms responsible for the increase in PBF at birth.

Before birth, the human fetus grows and develops in a completely liquid-filled environment. Thus, throughout the first 9 months of a humans life, gas exchange occurs across the placenta and not across the lungs, which are filled with liquid. In this period of life, the blood flow in the lungs is very low. At birth, the lungs must take over the responsibility of gas exchange and for this to occur 2 major changes must occur in the lung; 1. the lungs must clear themselves of liquid and be filled with air and 2. blood flow in the lungs, known as pulmonary blood flow, must rapidly increase. Despite its vital importance in the transition to newborn life, the factors regulating the increase in pulmonary blood flow at birth are still unclear. It has been previously thought that, at birth, starting ventilation stimulates a local increase in pulmonary blood flow and that the increase in blood flow is mainly in the aerated regions of the lungs as aeration and blood flow are usually kept closely matched in the adult. In a recent and unexpected finding, Stuart Hooper and his research group had shown that the increase in pulmonary blood flow is not spatially related to lung aeration and the role of increased oxygenation remains unclear. Therefore the main part of this project was to investigate the separate roles of lung aeration and increased oxygenation in the increase in pulmonary blood flow. This was done using simultaneous phase contrast X-ray imaging and angiography in preterm rabbit kittens. With this project we could confirm previous findings, which showed that the increase in pulmonary blood flow at birth is not spatially related to lung aeration. Limited aeration of the lungs leads to global pulmonary blood flow changes and this increase is unrelated to oxygenation, although oxygen can potentiate the increase. This indicates that a highly potent stimulus that is unrelated to oxygen can initiate the aeration-induced changes in pulmonary blood flow.