Grant: Operating Grant

Pulmonary edema describes an excess accumulation of fluid in the lungs. With increasing amounts of fluids in the lungs, gas exchange becomes impaired and patients ultimately die of respiratory failure. The current concept of pulmonary edema differentiates between two forms: In one case ("cardiogenic edema"), high blood pressure in the lung "squeezes" out fluid from the blood vessels into the air space. In the other case ("non-cardiogenic edema"), the blood vessels of the lung become "leaky" due to ongoing inflammatory responses, allowing fluid to leak from the blood vessels into the airspace. Here, we propose a third mechanism how pulmonary edema may evolve. We know that the epithelial cells outlining the air spaces can actively transport ions such as Na+ and Cl-. For osmotic reasons, this ion transport will be accompanied by a movement of fluid into the same direction. In healthy lungs, the epithelial cells of the distal air spaces absorb ions and thus, fluid, out of the airspace back into the blood. Here, we propose that in some disease conditions, the direction of this ion transport may reverse. As a result, the epithelial cells will start to move ion and thus, fluid, into the airspaces. Ultimately, this flooding of the airspaces will fatally impair breathing. In this proposal, we aim to i) consolidate this novel concept and test its validity for different forms of cardiogenic and non-cardiogenic edema, ii) elucidate the cellular mechanisms which cause the proposed reversal of ion and fluid transport, and iii) exploit this knowledge for the development of new treatment strategies for pulmonary edema. The results of this project are expected to profoundly change our understanding of one of the basic mechanisms of lung disease, i.e. pulmonary edema. They will provide new insights into the cellular mechanisms regulating the movement of ion and fluid. Importantly, we anticipate our findings to provide the basis for a better treatment of pulmonary edema.