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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Harabin, Andrea L
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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Hoegl, Sandra; Burns, Nana; Angulo, Martín et al. (2018) Capturing the multifactorial nature of ARDS - ""Two-hit"" approach to model murine acute lung injury. Physiol Rep 6:e13648
Hoegl, Sandra; Ehrentraut, Heidi; Brodsky, Kelley S et al. (2017) NK cells regulate CXCR2+ neutrophil recruitment during acute lung injury. J Leukoc Biol 101:471-480
Kork, F; Balzer, F; Krannich, A et al. (2017) Back-calculating baseline creatinine overestimates prevalence of acute kidney injury with poor sensitivity. Acta Physiol (Oxf) 219:613-624
Dehn, Shirley; DeBerge, Matthew; Yeap, Xin-Yi et al. (2016) HIF-2? in Resting Macrophages Tempers Mitochondrial Reactive Oxygen Species To Selectively Repress MARCO-Dependent Phagocytosis. J Immunol 197:3639-3649
Ferrari, Davide; McNamee, Eóin N; Idzko, Marco et al. (2016) Purinergic Signaling During Immune Cell Trafficking. Trends Immunol 37:399-411
Hoegl, Sandra; Zwissler, Bernhard; Eltzschig, Holger K et al. (2016) Acute respiratory distress syndrome following cardiovascular surgery: current concepts and novel therapeutic approaches. Curr Opin Anaesthesiol 29:94-100
Kiers, Harmke D; Scheffer, Gert-Jan; van der Hoeven, Johannes G et al. (2016) Immunologic Consequences of Hypoxia during Critical Illness. Anesthesiology 125:237-49
Garcia-Morales, Luis J; Chen, Ning-Yuan; Weng, Tingting et al. (2016) Altered Hypoxic-Adenosine Axis and Metabolism in Group III Pulmonary Hypertension. Am J Respir Cell Mol Biol 54:574-83
Ju, Cynthia; Colgan, Sean P; Eltzschig, Holger K (2016) Hypoxia-inducible factors as molecular targets for liver diseases. J Mol Med (Berl) 94:613-27
Neudecker, Viola; Brodsky, Kelley S; Kreth, Simone et al. (2016) Emerging Roles for MicroRNAs in Perioperative Medicine. Anesthesiology 124:489-506

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