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
Liu, Yuhong; Cole, Victoria; Lawandy, Isabella et al. (2018) Decreased coronary arteriolar response to KCa channel opener after cardioplegic arrest in diabetic patients. Mol Cell Biochem 445:187-194
Chorzalska, Anna; Ahsan, Nagib; Rao, R Shyama Prasad et al. (2018) Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK-ERK and NF-?B pathways in a model of chronic myeloid leukemia. Mol Oncol 12:630-647
Abbasi, Adeel; Devers, Cynthia; Muratore, Christopher S et al. (2018) Examining the role of extracorporeal membrane oxygenation in patients following suspected or confirmed suicide attempts: A case series. J Crit Care 44:445-449
Lu, Qing; Gottlieb, Eric; Rounds, Sharon (2018) Effects of cigarette smoke on pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol 314:L743-L756
Dennery, Phyllis A; Carr, Jennifer; Peterson, Abigail et al. (2018) THE ROLE OF MITOCHONDRIAL FATTY ACID USE IN NEONATAL LUNG INJURY AND REPAIR. Trans Am Clin Climatol Assoc 129:195-201
Banerjee, Debasree; Monaghan, Sean; Zhao, Runping et al. (2018) Soluble programmed cell death protein-1 and programmed cell death ligand-1 in sepsis. Crit Care 22:146
Harrington, Elizabeth O; Vang, Alexander; Braza, Julie et al. (2018) Activation of the sweet taste receptor, T1R3, by the artificial sweetener sucralose regulates the pulmonary endothelium. Am J Physiol Lung Cell Mol Physiol 314:L165-L176
Awad, Maan A; Aldosari, Sarah R; Abid, M Ruhul (2018) Genetic Alterations in Oxidant and Anti-Oxidant Enzymes in the Vascular System. Front Cardiovasc Med 5:107
Baird, Grayson L; Archer-Chicko, Christine; Barr, R Graham et al. (2018) Lower DHEA-S levels predict disease and worse outcomes in post-menopausal women with idiopathic, connective tissue disease- and congenital heart disease-associated pulmonary arterial hypertension. Eur Respir J 51:
Shah, Nishant R; Blankstein, Ron; Villines, Todd et al. (2018) Coronary CTA for Surveillance of Cardiac Allograft Vasculopathy. Curr Cardiovasc Imaging Rep 11:26

Showing the most recent 10 out of 96 publications