Acute hypoxemic respiratory failure (AHRF) is a life threatening condition associated with significant morbidity and mortality. Initially during AHRF, lung edema accumulates and impairs alveolar oxygen exchange unless mechanisms for edema clearance become effective. Recent studies have suggested that rapid edema clearance is associated with better outcomes in mechanically ventilated patients with AHRF. Lung edema clearance is driven predominantly by active Na+ transport out of the alveoli, mediated by apical Na+ channels and the basolaterally located Na,K-ATPases. Previous studies have demonstrated that increases in Na,K-ATPase activity in the alveolar epithelium are associated with increased lung edema clearance. Dopamine is frequently used in critically ill patients to increase diuresis; this effect is mediated by inhibition of renal Na,K-ATPase. However, we have demonstrated that dopamine increases edema clearance in the lungs. Thus, the focus of this application is to determine the mechanisms of dopamine-mediated regulation of lung edema clearance. We propose four specific aims to study the role of dopamine in the regulation of Na,K-ATPase in alveolar epithelial cells and its effects on active Na+ transport and lung edema clearance.
In Specific aim number 1, we will determine whether dopamine regulates Na,K-ATPase function via dopaminergic receptors in alveolar epithelial cells.
In Specific Aim number 2, we will determine whether dopamine (short-term) regulates Na,K-ATPase function by recruiting Na+ pumps from preexisting intracellular pools into the basolateral membrane of alveolar epithelial cells.
In Specific Aim number 3, we will determine whether dopamine (long term) regulates Na,K-ATPase function in alveolar epithelial cells via mitogen activated protein kinase (MAPK) pathways by increasing transcription of Na,K-ATPase genes.
In Specific Aim number 4, we will determine whether dopamine increases active Na+ transport and lung edema clearance in normal and injured rat lungs by upregulating alveolar epithelial cell Na,K-ATPase. Studies have been conducted for each of the specific aims and the preliminary results support our hypotheses and the feasibility of the proposed studies. Completion of the proposed experiments will provide novel information on the role of dopamine in the regulation of Na,K-ATPase and active Na+ transport in the alveolar epithelium which will help with the design of new strategies to enhance lung edema clearance in patients with hypoxemic respiratory failure.
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