Pulmonary edema is removed from the alveolar airspace by active Na+ transport by alveolar epithelial cells. It is intuitive that active transport increases epithelial cell energy consumption at times when cellular energy stores could be compromised. Data from a variety of experimental systems indicate that cells match energy consumption with energy supply by reducing active Na+ transport when energy stores are reduced. To date no such counter-regulatory mechanisms have been described in alveolar epithelial cells. Adenosine is produced from metabolism of AMP when intracellular ATP consumption and/or cAMP production are high. We speculate that increased levels of cAMP (from b-receptor signaling) and AMP/ADP (from Na,K-ATPase activity) in the setting of lung injury provide substrate for adenosine production in the alveolus. We recently noted that adenosine has concentration dependent, bidirectional effects on alveolar active Na+ transport in isolated rat lungs. Specifically, low concentrations of adenosine (=10-8M) increase alveolar active Na+ transport by ~100% via type 2a adenosine receptors (A2aR) whereas high concentrations (=10-6M) reduce it via type 1 adenosine receptors (A1R). We have also identified these receptors in distal rat and mouse lung tissue and isolated rat and mouse alveolar type 2 epithelial cells. These new observations are the first descriptions of a role for adenosine and its receptors in the alveolar epithelium and the first autocrine/paracrine mechanism that conditionally up- and down-regulates alveolar epithelial active Na+ transport. Based on this preliminary data, we hypothesize that: Alveolar epithelial adenosine receptors participate in the regulation of active Na+ transport in normal and injured lungs. The known inter-relationship of adenosine with cAMP production and ATP consumption and our preliminary data cause us to propose a new paradigm of regulation of alveolar active Na+ transport. Specifically, we believe that in normal lung alveolar adenosine concentrations in the extracellular space are low and serve as a positive modulator of alveolar active Na+ transport, probably via an A2aR dependent pathway. Conversely, during lung injury high ATP utilization and cAMP production lead to extracellular adenosine concentrations sufficient to inhibit adenylyl cyclase and reduce active transport via an A1R dependent pathway. This model suggests that adenosine and its receptors participate in a feedback loop that allows alveolar epithelial cells to fine tune cAMP sensitive active Na+ transport in response to changes in ATP utilization and/or cAMP production. To test our hypothesis we are proposing the following 3 scientific aims:
Aim 1 : Characterize adenosine receptors in the alveolar epithelium and determine if, and how, they regulate alveolar active Na+ transport in normal lungs.
Aim 2 : Determine the mechanism(s) by which adenosine receptors modulate alveolar active Na+ transport.
Aim 3 : Determine if alveolar epithelial adenosine receptor signaling is protective or maladaptive during acute lung injury. The focused studies we are proposing integrate pharmacologic manipulations, genetically engineered mice, and gene transfer with physiologic models to generate models of gain and loss of epithelial adenosine receptor function that will allow us to test our hypothesis and to determine if adenosine receptors serve protective or maladaptive roles in the alveolar epithelium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079094-04
Application #
7333233
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2005-01-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2009-12-31
Support Year
4
Fiscal Year
2008
Total Cost
$378,750
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Factor, Phillip; Mutlu, Goskhan M; Chen, Lan et al. (2007) Adenosine regulation of alveolar fluid clearance. Proc Natl Acad Sci U S A 104:4083-8