Regulatory mechanisms of fluid clearance and lung function by alveolar ion channels

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Lung function is dependent on alveolar epithelial cells that are responsible for surfactant production and transepithelial ion/liquid transport. Indeed, fluid clearance is required to maintain alveolar spaces virtually free of liquid, which is necessary for gas exchange. It has been established that liquid absorption is mainly driven by active ion transport through the Na+ channel ENaC. However, the complex regulatory mechanisms of ENaC and Na+/fluid transport remain incompletely understood.***Over the terms of our previous NSERC grants, we have made significant progress in the understanding of the mechanisms regulating ENaC channels and Na+/liquid transport through primary alveolar type II (ATII) cells. Our work also unveiled another class of channels, i.e. K+ channels (KCh, namely KATP and KvQT1 channels) that regulates ENaC expression via changes in promoter activity and participate in the control of Na+/liquid absorption. Finally, we have implemented an integrative murine model to study the clearance of fluids and lung function parameters. Our preliminary in vivo data indicated a relationship between ENaC and KCh and a control of alveolar fluid clearance, surfactant expression and lung compliance by KCh. We now propose to pursue our research program to dissect the complementary roles of ENaC and KCh in the control of fluid absorption and lung function using both cellular and animal models.****Our first goal will be to investigate, at the cellular level: 1) the signals controlling ENaC expression and the region of the ENaC promoter involved in ENaC regulation by KCh and 2) the complementary function, and relative contribution, of ENaC and KCh, on liquid absorption through ATII cells under basal conditions as well as following stimulation with -adrenergic agonists or corticosteroids. Expression of surfactant proteins will also be evaluated. Our second aim will be to pursue our in vivo studies in mice after ion channel silencing, or conversely after instillation of pharmacological compounds stimulating Na+ and K+ transport. Based on our in vitro observation showing a relationship between KCh function and ENaC expression, we will measure the level of expression of ion channels and transporters involved in alveolar clearance in situ. Finally, we will define the physiological effects of ENaC and KCh modulation on liquid clearance, surfactant production, lung function parameters as well as blood gases; in basal conditions and after stimulation with -adrenergic agonists or corticosteroids.***Our research program will allow a better understanding of the regulatory mechanisms responsible for the control of major functions of alveolar cells in lung epithelial physiology, in non-pathological conditions. Combining molecular and cellular aspects as well as an integrative model to study lung physiology in mice, our NSERC program also provides high level, multidisciplinary training to HQP in our lab.**