The deleterious effects of hypercapnia on the lungs

Hypercapnia (high pCO2) is observed in patients with lung diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, broncho-pulmonary dysplasia and advanced neuromuscular diseases. Also, "permissive hypercapnia” is the prevalent paradigm in mechanically ventilated patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) which has been supported by earlier studies suggesting that high CO2 levels could have beneficial effects on lung injury. More recently the notion of "permissive hypercapnia" has been challenged by our and other investigators studies who reported that elevated pCO2 can have deleterious effects on alveolar epithelial function and host immunity. In preparation for this proposal, we have conducted preliminary studies and the data suggest that exposing alveolar epithelial cells and mice to high CO2 levels decreases epithelial cell migration and proliferation, thus, impairing lung injury repair as well as cause diaphragm muscle dysfunction. These data is of clinical relevance, as it is recognized that patients with chronic lung diseases and hypercapnia have worse outcomes. As such, in this application we propose to determine the mechanisms by which hypercapnia contributes to impaired recovery from lung injury and leads to diaphragm muscle degradation and impaired muscle regeneration. We will study the effects of high CO2 levels on the lungs via three interrelated aims: in experiments pertaining to specific aim # 1, we will determine whether high CO2 levels inhibit cell migration via miR-183/96/182 cluster; in experiments pertaining to specific aim #2, we will determine whether hypercapnia leads to inhibition of Rac1 and impairs cell migration and lung injury repair and in studies pertaining specific aim # 3,we will determine whether hypercapnia leads to diaphragm dysfunction via induction of the ubiquitin/proteasomal pathway and impaired regeneration. We have conducted preliminary experiments for each of the specific aims which support the feasibility of this grant proposal. The proposed experiments will generate novel information on the effects of hypercapnia on alveolar epithelial and diaphragm function which is of clinical significance in patients with ARDS/ALI on mechanical ventilation and hypercapnic patients with COPD, bronchopulmonary dysplasia and cystic fibrosis.