Plasma adenosine is increased in sepsis-induced acute lung injury (ALI). Sustained elevation of adenosine in adenosine deaminase (ADA-/-) mice causes increased permeability lung edema. ADA activity is decreased in rats and humans by cigarette smoke (CS) exposure, a risk Specific Aim 1 will determine the extent to which ENT1 and oxidative stress mediate sustained elevated adenosine-induced lung edema in animal models.
Specific Aim 2 will identify the mechanism of deleterious effects of sustained exposure to elevated adenosine on barrier function in cultured lung microvascular endothelial cells (LMVEC). I anticipate that sustained exposure to elevated adenosine causes ENT1-mediated disruption of EC barrier function and lung edema and that CS increases adenosine and similarly disrupts EC barrier function. The approach is innovative since it uses ADA deficiency as a model for sustained adenosine elevation and a novel model of CS priming ALI. These studies will elucidate a novel pathway for adenosine effects mediated by intracellular uptake of adenosine. Inhibition of ENT1- facilitated adenosine transport and downstream signaling may likely provide significant and greatly needed new approaches to treat diseases associated with sustained elevated adenosine and CS exposure.

Public Health Relevance

Adenosine can protect against acute lung injury at acute exposure, but worsens lung injury with prolonged exposure. The objectives of this study are to understand the mechanism of sustained adensoine exposure - induced lung edema and its role in cigarette smoke priming lung injury. The findings may provide innovative treatment options for lung diseases associated with tobacco smoke and sustained elevated adenosine.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103652-02
Application #
8735962
Study Section
Special Emphasis Panel (ZGM1-TWD-B)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$212,912
Indirect Cost
$43,721
Name
Ocean State Research Institute, Inc.
Department
Type
DUNS #
848476271
City
Providence
State
RI
Country
United States
Zip Code
02908
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