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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2024-2035. Prepublished online as a Blood First Edition Paper on December 4, 2007; DOI 10.1182/blood-2007-10-117044. This Article Full Text (PDF) All Versions of this Article: blood-2007-10-117044v1 111/4/2024    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Eckle, T. Articles by Eltzschig, H. K. Search for Related Content PubMed PubMed Citation Articles by Eckle, T. Articles by Eltzschig, H. K. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 9, 2007 Accepted November 29, 2007 A2B adenosine receptor dampens hypoxia-induced vascular leak Tobias Eckle, Marion Faigle, Almut Grenz, Stefanie Laucher, Linda F. Thompson, and Holger K. Eltzschig* Department of Anesthesiology and Intensive Care Medicine, Tubingen University Hospital, Tubingen, Germany Department of Pharmacology and Toxicology, Tubingen University Hospital, Tubingen, Germany Immunobiology and Cancer Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, OK, United States Mucosal Inflammation Program, Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Sciences Center, Denver, CO, United States * Corresponding author; email: holger.eltzschig{at}uchsc.edu. Extracellular adenosine has been implicated in adaptation to hypoxia and previous studies demonstrated a central role in vascular responses. Here, we examined the contribution of individual adenosine receptors (A1AR/A2AAR/A2BAR/A3AR) to vascular leak induced by hypoxia. Initial profiling studies revealed that siRNA-mediated repression of the A2BAR selectively increased endothelial leak in response to hypoxia in vitro. In parallel, vascular permeability was significantly increased in vascular organs of A2BAR-/--mice subjected to ambient hypoxia (8% oxygen, 4h; e.g. lung: 2.1±0.12-fold increase). By contrast, hypoxia-induced vascular leak was not accentuated in A1AR-/--, A2AAR-/--, or A3AR-/--deficient mice, suggesting a degree of specificity for the A2BAR. Further studies in wild type mice revealed that the selective A2BAR antagonist PSB1115 resulted in profound increases in hypoxia-associated vascular leakage while A2BAR agonist (BAY60-6583) treatment was associated with almost complete reversal of hypoxia-induced vascular leakage (e.g. lung: 2.0±0.21-fold reduction). Studies in bone marrow chimeric A2BAR mice suggested a predominant role of vascular A2BARs in this response, while hypoxia-associated increases in tissue neutrophils were, at least in part, mediated by A2BAR expressing hematopoietic cells. Taken together, these studies provide pharmacological and genetic evidence for vascular A2BAR signaling as central control point of hypoxia-associated vascular leak. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Eckle, M. Koeppen, and H. K. Eltzschig Role of Extracellular Adenosine in Acute Lung Injury Physiology, October 1, 2009; 24(5): 298 - 306. [Abstract] [Full Text] [PDF] A. Zarbock, M. R. DiStasi, E. Smith, J. M. Sanders, G. Kronke, B. L. Harry, S. von Vietinghoff, K. Buscher, J. L. Nadler, and K. Ley Improved Survival and Reduced Vascular Permeability by Eliminating or Blocking 12/15-Lipoxygenase in Mouse Models of Acute Lung Injury (ALI) J. Immunol., October 1, 2009; 183(7): 4715 - 4722. [Abstract] [Full Text] [PDF] R. E. Cagnina, S. I. Ramos, M. A. Marshall, G. Wang, C. R. Frazier, and J. Linden Adenosine A2B receptors are highly expressed on murine type II alveolar epithelial cells Am J Physiol Lung Cell Mol Physiol, September 1, 2009; 297(3): L467 - L474. [Abstract] [Full Text] [PDF] Y. Zhou, A. Mohsenin, E. Morschl, H. W. J. Young, J. G. Molina, W. Ma, C.-X. Sun, H. Martinez-Valdez, and M. R. Blackburn Enhanced Airway Inflammation and Remodeling in Adenosine Deaminase-Deficient Mice Lacking the A2B Adenosine Receptor J. Immunol., June 15, 2009; 182(12): 8037 - 8046. [Abstract] [Full Text] [PDF] Q. Liu, J. Li, J. Khoury, S. P. Colgan, and J. C. Ibla Adenosine Signaling Mediates SUMO-1 Modification of I{kappa}B{alpha} during Hypoxia and Reoxygenation J. Biol. Chem., May 15, 2009; 284(20): 13686 - 13695. [Abstract] [Full Text] [PDF] J.-S. Frick, C. F. MacManus, M. Scully, L. E. Glover, H. K. Eltzschig, and S. P. Colgan Contribution of Adenosine A2B Receptors to Inflammatory Parameters of Experimental Colitis J. Immunol., April 15, 2009; 182(8): 4957 - 4964. [Abstract] [Full Text] [PDF] M. L. Hart, B. Jacobi, J. Schittenhelm, M. Henn, and H. K. Eltzschig Cutting Edge: A2B Adenosine Receptor Signaling Provides Potent Protection during Intestinal Ischemia/Reperfusion Injury J. Immunol., April 1, 2009; 182(7): 3965 - 3968. [Abstract] [Full Text] [PDF] J.-N. Yang, J.-F. Chen, and B. B. Fredholm Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H1141 - H1149. [Abstract] [Full Text] [PDF] J. Reutershan, I. Vollmer, S. Stark, R. Wagner, K.-C. Ngamsri, and H. K. Eltzschig Adenosine and inflammation: CD39 and CD73 are critical mediators in LPS-induced PMN trafficking into the lungs FASEB J, February 1, 2009; 23(2): 473 - 482. 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