Extracellular nucleotides liberated at inflammatory tissue sites are metabolized to adenosine by surface expressed ecto-nucleotidases (CD73 and CD39). Ongoing studies indicate that adenosine liberated by this process is available to activate surface adenosine receptors (A1AR, A2AAR, A2BAR, A3AR), and has been shown to attenuate acute lung injury. In the present study, we will use in vitro models of mechanical stretch and murine ventilator induced lung injury to study adenosine-tissue protection during ALI. Preliminary studies indicate a contribution of pulmonary CD39 and CD73 as control points for generation of extracellular adenosine during VILI. Moreover, studies in gene-targeted mice for individual ARs suggest a prominent role of A2BAR signaling for lung protection during VILI. Thus, we will pursue work toward: A) Defining details of extracellular adenosine generation during mechanical stretch or VILI;B) Define transcriptonal regulation and consequences of signaling through ARs during VILI;and C) Extend evidence for a role of adenosine generation and signaling as therapy of VILI. We expect that these studies will shed new light on molecular mechanisms through which cyclic stretch as occurs during mechanical ventilation elevates extracellular adenosine levels as a tissue protective mechanism. We will have developed strategies that utilize these mechanisms to attenuate inflammation and capillary-alveolar leakage during VILI. Taken together, these studies will lay the groundwork for novel and specific therapeutic approaches in the treatment of acute lung injury.

Public Health Relevance

These studies will lay the groundwork for novel and specific therapeutic approaches in the treatment of acute lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092188-05
Application #
8423734
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2009-04-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$345,513
Indirect Cost
$109,893
Name
University of Colorado Denver
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Bartels, Karsten; Grenz, Almut; Eltzschig, Holger K (2014) Sphingosine-1-phosphate receptor signaling during acute kidney injury: the tissue is the issue. Kidney Int 85:733-5
Bartels, Karsten; Grenz, Almut; Eltzschig, Holger K (2014) Transforming high risk to high yield. Anesthesiology 120:1072-4
Eckle, Tobias; Kewley, Emily M; Brodsky, Kelley S et al. (2014) Identification of hypoxia-inducible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury. J Immunol 192:1249-56
Idzko, Marco; Ferrari, Davide; Eltzschig, Holger K (2014) Nucleotide signalling during inflammation. Nature 509:310-7
Eltzschig, Holger K; Bratton, Donna L; Colgan, Sean P (2014) Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat Rev Drug Discov 13:852-69
Ning, Chen; Wen, Jiaming; Zhang, Yujin et al. (2014) Excess adenosine A2B receptor signaling contributes to priapism through HIF-1? mediated reduction of PDE5 gene expression. FASEB J 28:2725-35
Bartels, Karsten; Sullivan, Breandan L; Eltzschig, Holger K (2014) TnT: blowing the cover from perioperative myocardial injury. Anesthesiology 120:533-5
Eltzschig, Holger K (2013) Extracellular adenosine signaling in molecular medicine. J Mol Med (Berl) 91:141-6
Ehrentraut, Heidi; Clambey, Eric T; McNamee, Eoin N et al. (2013) CD73+ regulatory T cells contribute to adenosine-mediated resolution of acute lung injury. FASEB J 27:2207-19
Poth, Jens M; Brodsky, Kelley; Ehrentraut, Heidi et al. (2013) Transcriptional control of adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease. J Mol Med (Berl) 91:183-93

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