Adenosine signaling during acute and chronic disease states
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REVIEW
Adenosine signaling during acute and chronic disease states Harry Karmouty-Quintana & Yang Xia & Michael R. Blackburn
Received: 6 November 2012 / Revised: 4 January 2013 / Accepted: 8 January 2013 / Published online: 23 January 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Adenosine is a signaling nucleoside that is produced following tissue injury, particularly injury involving ischemia and hypoxia. The production of extracellular adenosine and its subsequent signaling through adenosine receptors plays an important role in orchestrating injury responses in multiple organs. There are four adenosine receptors that are widely distributed on immune, epithelial, endothelial, neuronal,and stromal cells throughout the body. Interestingly, these receptors are subject to altered regulation following injury. Studies in mouse models and human cells and tissues have identified that the production of adenosine and its subsequent signaling through its receptors plays largely beneficial roles in acute disease states, with the exception of brain injury. In contrast, if elevated adenosine levels are sustained beyond the acute injury phase, adenosine responses can become detrimental by activating pathways that promote tissue injury and fibrosis. Understanding when during the course of disease adenosine signaling is beneficial as opposed to detrimental and defining the mechanisms involved will be critical for the advancement of adenosine-based therapies for acute and chronic diseases. The purpose of this review is to discuss key observations that define the beneficial and detrimental aspects of adenosine signaling during acute and chronic disease states with an emphasis on cellular processes, such as inflammatory cell regulation, vascular barrier function, and tissue fibrosis. Keywords Adenosine receptors . Inflammation . Fibrosis . Vascular barrier function . CD73 . ADORA2B . ADORA2A . ADORA3 . ADORA1 . Acute lung injury . Remodeling . Anti-inflammatory H. Karmouty-Quintana : Y. Xia : M. R. Blackburn (*) Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, 6431 Fannin Blvd, Suite 6.200, Houston, TX 77030, USA e-mail: [email protected]
Introduction Tissue responses to ischemia, acute inflammation, or fibrosis involve severe levels of hypoxia [1]. Studies over the past decade provide strong evidence that cellular responses to hypoxia include robust increases in extracellular adenosine and signaling events through adenosine receptors. In acute injury settings, this hypoxic adenosine response activates pathways that promote tissue adaptation during hypoxia [1]. These pathways include restoration of normal oxygen levels, enhancing metabolic ischemia tolerance, and dampening inflammation. Indeed, preclinical studies show that adenosine signaling is beneficial in ischemic acute injury in the lung [2–6], kidney [7–9], heart [10, 11], gastrointestinal track [12], and liver [13]. However, if elevated adenosine levels are sustained beyond the acute injury phase, h
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