Grant: Operating Grant

Hypoxic pulmonary vasoconstriction is the mechanism by which the lung redistributes blood flow from poorly ventilated to better aerated areas. This effect is important to improve gas exchange and oxygen uptake. However, the signaling pathways underlying this response are far from clear. Here, we hypothesize that sphingolipids play an important role as signaling molecules in hypoxic pulmonary vasoconstriction. Sphingolipids are an important lipid component of the cell membrane, and determine the formation of so called lipid rafts. These lipid rafts are small microdomains which serve as integrative clusters for many signaling molecules. Some sphingolipids can traffic through the cell membrane via a transporter protein called cystic fibrosis transmembrane conductance regulator (CFTR). Mutations in the CFTR gene cause the fatal disease cystic fibrosis. Importantly, patients with cystic fibrosis have problems to optimize their pulmonary gas exchange, suggesting their hypoxic pulmonary vasoconstriction response may be impaired. Hypoxic pulmonary vasoconstriction is also blocked in patients infected with the bacterium Pseudomonas aeruginosa, which secretes a factor that inhibits CFTR. Therefore, we propose sphingolipid signaling through CFTR as an important mechanism to optimize gas exchange in the lung. Using a combination of state-of-the-art analytical techniques in cultured cells, isolated organs and experimental animal models, we will put this hypothesis to the test. The results of this project are expected to profoundly expand our understanding of one of the basic regulatory mechanisms of lung function and gas exchange. The identification of a critical role for CFTR in hypoxic pulmonary vasoconstriction is expected to open new therapeutic strategies to improve gas exchange in patients with cystic fibrosis or Pseudomonas aeruginosa infections. In this way, the proposed research will improve public health, and decrease future health care costs and disabiliti