Grant: Project Grant

Acute respiratory distress syndrome (ARDS) is a devastating form of respiratory failure. Although the causes of ARDS may be multiple (infection, near drowning, physical trauma...), its initial phase commonly features severe injury of the epithelial cell layer lining lung alveoli, accumulation of liquid in the lungs (edema), massive inflammation and respiratory failure. No specific treatment exists for ARDS and the mortality rates remain unacceptably high (25- 45%). Improvement in survival and rapid recovery from ARDS relies on the development of novel therapies favoring the restoration of alveolar integrity and the subsequent resolution of initial phase of ARDS. Importantly, we discovered that a specific class of proteins transporting potassium (K+ channels) through alveolar epithelial cells plays a key role in alveolar repair. In addition, we have accumulated data from animal models which strongly support that these channels are not only crucial for the restoration of alveolar integrity but are also implicated in the resorption of lung edema and inflammation. Therefore, we propose that targeting K+ channels will promote alveolar integrity and lung function, then favoring ARDS resolution. Our main goal is to address key questions regarding the mode of action of K+ channels in the resolution of ARDS parameters. At the cellular level, we will dissect the mechanisms on how K+ channels control alveolar repair processes 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 will then be 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.