Grant: Operating Grant - PA: Regional Partnership Program : Manitoba

The newborn lung is very sensitive to low oxygen levels. In the lungs of infants who do not receive sufficient oxygen at birth, low oxygen makes the lung blood vessels go into spasm, so blood cannot flow through the lung for gas exchange. This causes the lethal disease persistent pulmonary hypertension of the newborn (PPHN). We are studying the effects of low oxygen levels on the function of muscle lining the blood vessels of the newborn lung. Our lab has shown that in low oxygen, muscle cells in lung blood vessels quickly become hypersensitive to agents of inflammation, such as thromboxane. This sensitivity does not reverse even after oxygen is restored. Sensitized muscle cells are more prone to cause blood vessel spasm. Chemical changes in the thromboxane receptor protein determine how well the receptor can bind to inflammation molecules in the circulation, and how the activation of this receptor raises lung blood pressure. Chemical changes also allow the receptor to select which kind of signals it will release into the muscle cell when it is stimulated. Some of these protein changes could be increased by a low oxygen environment, such as in PPHN. We induce the disease PPHN in newborn animals by raising them in a low oxygen environment for 72 hours. We also model PPHN in muscle cells from the lungs of newborn piglets, growing them in a low oxygen environment for the same time period. Using muscle cells or arteries from these models, and also by studying specially modified receptor proteins constructed in the lab, we will study [i] the role of thromboxane in regulating pathways that control muscle contraction and muscle cell structure, and [ii] whether chemical changes in the thromboxane receptor can alter its ability to increase blood pressure in lung arteries, under normal or low oxygen conditions. Knowledge of pathways causing lung blood vessel spasm will improve treatment options for the one third of PPHN babies who cannot respond to current therapy.