Patients with acute lung injury and acute respiratory distress syndrome (ARDS), develop pulmonary edema that impairs 02 exchange resulting in significant morbidity and mortality. It has been reported that increased edema clearance is associated with better outcomes of patients with ARDS. Lung liquid clearance is driven predominantly by active Na+ transport, mediated by apical Na+ channels and the basolateral Na, K-ATPases of alveolar epithelial cells. Dopamine (DA) is used in ARDS and other critically ill patients to increase diuresis; this effect is due to inhibition of renal Na,K-ATPase. However, we have reported that dopamine upregulated the Na,KATPase in the alveolar epithelium which is increased lung liquid clearance. The focus of this application is to elucidate mechanisms by which activation of dopaminergic D1 receptor regulates Na,KATPase function. Specifically, we propose studies to determine mechanisms regulating the dopaminergic effects on the alveolar epithelial cell Na,KATPase which contributes to active Na+ transport and lung liquid clearance, by four specific aims.
In Specific aim # 1, we will determine whether dopamine regulates Na,K-ATPase function via protein phosphatase 2A-mediated dephosphorylation of the Na+ pump in alveolar epithelial cells.
In Specific Aim #2, we will determine the mechanisms by which dopamine regulates the traffic of Na, K-ATPase proteins (by real time analysis) from endosomal compartments into the basolateral membrane of alveolar epithelial cells.
In Specific Aim #3, we will determine whether dopamine is produced by the alveolar epithelium and whether the endogenous dopamine increases Na,K-ATPase function and lung liquid clearance.
In Specific Aim # 4, we will determine the role of the dopaminergic receptor D1 on lung liquid clearance. Experiments in this aim will use adenoviral overexpression of the dopaminergic D1 receptor in rat lungs and D1A receptor """"""""knock-out"""""""" mice to study lung liquid clearance. Studies have been conducted for each of the specific aims and the preliminary data support our hypotheses and the feasibility of the proposed studies. Completion of the proposed experiments will provide novel important information on the mechanisms of dopamine-mediated regulation of the Na,K-ATPase and active Na+ transport in the alveolar epithelium. This information may be of clinical relevance in the design of new approaches to increase lung edema clearance.
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