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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Special Emphasis Panel (ZGM1-TWD-B)
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Ocean State Research Institute, Inc.
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