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1.
J Immunol ; 192(3): 1249-56, 2014 Feb 01.
Article in English | MEDLINE | ID: mdl-24391213

ABSTRACT

Although acute lung injury (ALI) contributes significantly to critical illness, resolution often occurs spontaneously through endogenous pathways. We recently found that mechanical ventilation increases levels of pulmonary adenosine, a signaling molecule known to attenuate lung inflammation. In this study, we hypothesized a contribution of transcriptionally controlled pathways to pulmonary adenosine receptor (ADOR) signaling during ALI. We gained initial insight from microarray analysis of pulmonary epithelia exposed to conditions of cyclic mechanical stretch, a mimic for ventilation-induced lung disease. Surprisingly, these studies revealed a selective induction of the ADORA2B. Using real-time RT-PCR and Western blotting, we confirmed an up to 9-fold induction of the ADORA2B following cyclic mechanical stretch (A549, Calu-3, or human primary alveolar epithelial cells). Studies using ADORA2B promoter constructs identified a prominent region within the ADORA2B promoter conveying stretch responsiveness. This region of the promoter contained a binding site for the transcription factor hypoxia-inducible factor (HIF)-1. Additional studies using site-directed mutagenesis or transcription factor binding assays demonstrated a functional role for HIF-1 in stretch-induced increases of ADORA2B expression. Moreover, studies of ventilator-induced lung injury revealed induction of the ADORA2B during ALI in vivo that was abolished following HIF inhibition or genetic deletion of Hif1a. Together, these studies implicate HIF in the transcriptional control of pulmonary adenosine signaling during ALI.


Subject(s)
Acute Lung Injury/physiopathology , Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Receptor, Adenosine A2B/genetics , Stress, Mechanical , Ventilator-Induced Lung Injury/physiopathology , Acute Lung Injury/metabolism , Adenosine/physiology , Animals , Binding Sites , Cells, Cultured , Epithelial Cells/physiology , Female , Genes, Reporter , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/deficiency , Lung/metabolism , Lung/physiopathology , Male , Mice , Mice, Knockout , Mice, Transgenic , Promoter Regions, Genetic/genetics , Receptor, Adenosine A2B/biosynthesis , Receptor, Adenosine A2B/physiology , Transcription, Genetic
2.
Biochim Biophys Acta ; 1808(5): 1329-39, 2011 May.
Article in English | MEDLINE | ID: mdl-20546702

ABSTRACT

Since its discovery as a low-affinity adenosine receptor (AR), the A2B receptor (A2BAR), has proven enigmatic in its function. The previous discovery of the A2AAR, which shares many similarities with the A2BAR but demonstrates significantly greater affinity for its endogenous ligand, led to the original perception that the A2BAR was not of substantial physiologic relevance. In addition, lack of specific pharmacological agents targeting the A2BAR made its initial characterization challenging. However, the importance of this receptor was reconsidered when it was observed that the A2BAR is highly transcriptionally regulated by factors implicated in inflammatory hypoxia. Moreover, the notion that during ischemia or inflammation extracellular adenosine is dramatically elevated to levels sufficient for A2BAR activation, indicated that A2BAR signaling may be important to dampen inflammation particularly during tissue hypoxia. In addition, the recent advent of techniques for murine genetic manipulation along with development of pharmacological agents with enhanced A2BAR specificity has provided invaluable tools for focused studies on the explicit role of A2BAR signaling in different disease models. Currently, studies performed with combined genetic and pharmacological approaches have demonstrated that A2BAR signaling plays a tissue protective role in many models of acute diseases e.g. myocardial ischemia, or acute lung injury. These studies indicate that the A2BAR is expressed on a wide variety of cell types and exerts tissue/cell specific effects. This is an important consideration for future studies where tissue or cell type specific targeting of the A2BAR may be used as therapeutic approach.


Subject(s)
Receptor, Adenosine A2B/metabolism , Signal Transduction , Animals , Humans
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