Grant: Project Grant

Acute respiratory distress syndrome (ARDS) is a devastating form of respiratory failure in adults and children. Although ARDS causes may be multiple (infection, trauma, transplantation...), this syndrome initially commonly features severe injury of the epithelial cell layer lining alveoli, accumulation of liquid in the lungs (edema) and massive inflammation. Rapid resolution is pivotal for ARDS. If not, a fibrotic process rapidly arises, ultimately leading to respiratory failure. No specific treatment exists for ARDS and mortality rates remain unacceptably high. Improvement in survival relies on the development of novel therapies favoring the restoration of alveolar integrity, before establishment of fibrosis. Importantly, we discovered that a specific class of proteins transporting potassium (K+ channels) through alveolar epithelial cells plays key role in alveolar repair. In addition, our data from animal models strongly support that these channels are not only crucial to favor alveolar integrity but are also implicated in resorption of lung edema and inflammation. Therefore, we propose that targeting K+ channels will promote alveolar integrity and lung function, favoring ARDS resolution. Our main goal is to address key questions regarding the mode of action of alveolar K+ channels in the resolution of ARDS parameters. At the cellular level, we will dissect the mechanisms on how K+ channels regulate alveolar epithelial repair and we will study the relationship between K+ channel function and inflammation. Using complementary genetic and pharmacological strategies in animal models of ARDS, our aim is then to demonstrate the role of K+ channels in the resolution of ARDS parameters, through improvement of alveolar epithelial integrity and function. In summary, our project will provide a comprehensive knowledge of the action mechanisms of K+ channels for the resolution of ARDS and important insights into the development of innovative therapeutic strategies.