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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL065161-01
Application #
2743170
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1999-09-01
Project End
2003-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Vadasz, Istvan; Raviv, Stacy; Sznajder, Jacob I (2007) Alveolar epithelium and Na,K-ATPase in acute lung injury. Intensive Care Med 33:1243-51
Lecuona, Emilia; Dada, Laura A; Sun, Haiying et al. (2006) Na,K-ATPase alpha1-subunit dephosphorylation by protein phosphatase 2A is necessary for its recruitment to the plasma membrane. FASEB J 20:2618-20
Mutlu, Gokhan M; Sznajder, Jacob I (2005) Mechanisms of pulmonary edema clearance. Am J Physiol Lung Cell Mol Physiol 289:L685-95
Bertorello, Alejandro M; Sznajder, Jacob I (2005) The dopamine paradox in lung and kidney epithelia: sharing the same target but operating different signaling networks. Am J Respir Cell Mol Biol 33:432-7
Sloniewsky, Daniel E; Ridge, Karen M; Adir, Yochai et al. (2004) Leukotriene D4 activates alveolar epithelial Na,K-ATPase and increases alveolar fluid clearance. Am J Respir Crit Care Med 169:407-12
Dada, Laura A; Sznajder, Jacob I (2003) Mechanisms of pulmonary edema clearance during acute hypoxemic respiratory failure: role of the Na,K-ATPase. Crit Care Med 31:S248-52
Bertorello, Alejandro M; Komarova, Yulia; Smith, Kristen et al. (2003) Analysis of Na+,K+-ATPase motion and incorporation into the plasma membrane in response to G protein-coupled receptor signals in living cells. Mol Biol Cell 14:1149-57
Sznajder, J I; Factor, P; Ingbar, D H (2002) Invited review: lung edema clearance: role of Na(+)-K(+)-ATPase. J Appl Physiol 93:1860-6
Saldias, F J; Comellas, A P; Pesce, L et al. (2002) Dopamine increases lung liquid clearance during mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 283:L136-43
Ridge, Karen M; Dada, Laura; Lecuona, Emilia et al. (2002) Dopamine-induced exocytosis of Na,K-ATPase is dependent on activation of protein kinase C-epsilon and -delta. Mol Biol Cell 13:1381-9

Showing the most recent 10 out of 19 publications