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 #
1P20GM103652-01A1
Application #
8465677
Study Section
Special Emphasis Panel (ZGM1-TWD-B (CB))
Project Start
Project End
Budget Start
2013-09-20
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$180,120
Indirect Cost
$10,506
Name
Ocean State Research Institute, Inc.
Department
Type
DUNS #
848476271
City
Providence
State
RI
Country
United States
Zip Code
02908
Aliotta, Jason M; Pereira, Mandy; Wen, Sicheng et al. (2016) Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice. Cardiovasc Res 110:319-30
(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Heydari, Bobak; Abdullah, Shuaib; Pottala, James V et al. (2016) Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial. Circulation 134:378-91
Monaghan, Sean F; Chung, Chun-Shiang; Chen, Yaping et al. (2016) Soluble programmed cell death receptor-1 (sPD-1): a potential biomarker with anti-inflammatory properties in human and experimental acute respiratory distress syndrome (ARDS). J Transl Med 14:312
Sakhatskyy, Pavlo; Wang, Zhengke; Borgas, Diana et al. (2016) Double-Hit Mouse Model of Cigarette Smoke Priming for Acute Lung Injury. Am J Physiol Lung Cell Mol Physiol :ajplung.00436.2016
Addison, Daniel; Farhad, Hoshang; Shah, Ravi V et al. (2016) Effect of Late Gadolinium Enhancement on the Recovery of Left Ventricular Systolic Function After Pulmonary Vein Isolation. J Am Heart Assoc 5:
Lomas-Neira, Joanne L; Heffernan, Daithi S; Ayala, Alfred et al. (2016) BLOCKADE OF ENDOTHELIAL GROWTH FACTOR, ANGIOPOIETIN-2, REDUCES INDICES OF ARDS AND MORTALITY IN MICE RESULTING FROM THE DUAL-INSULTS OF HEMORRHAGIC SHOCK AND SEPSIS. Shock 45:157-65
Feng, Jun; Liu, Yuhong; Sabe, Ashraf A et al. (2016) Differential impairment of adherens-junction expression/phosphorylation after cardioplegia in diabetic versus non-diabetic patients. Eur J Cardiothorac Surg 49:937-43
Korre, Maria; Porto, Luiz Guilherme G; Farioli, Andrea et al. (2016) Effect of Body Mass Index on Left Ventricular Mass in Career Male Firefighters. Am J Cardiol 118:1769-1773
Yoon, Pyoung Oh; Park, Jin Wook; Lee, Chang-Min et al. (2016) Self-assembled Micelle Interfering RNA for Effective and Safe Targeting of Dysregulated Genes in Pulmonary Fibrosis. J Biol Chem 291:6433-46

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