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Blood, 15 December 2004, Vol. 104, No. 13, pp. 3986-3992.
Prepublished online as a Blood First Edition Paper on August 19, 2004; DOI 10.1182/blood-2004-06-2066.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism
Holger K. Eltzschig,
Linda F. Thompson,
Jorn Karhausen,
Richard J. Cotta,
Juan C. Ibla,
Simon C. Robson, and
Sean P. Colgan
From the Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Immunobiology and Cancer Program Oklahoma Medical Research Foundation, Oklahoma City, OK; Department of Anesthesiology Children's Hospital, Harvard Medical School, Boston, MA; Transplantation Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; and Department of Anesthesiology, Tübingen University Hospital, Tübingen, Germany.
Hypoxia is a well-documented inflammatory stimulus and results in tissue polymorphonuclear leukocyte (PMN) accumulation. Likewise, increased tissue adenosine levels are commonly associated with hypoxia, and given the anti-inflammatory properties of adenosine, we hypothesized that adenosine production via adenine nucleotide metabolism at the vascular surface triggers an endogenous anti-inflammatory response during hypoxia. Initial in vitro studies indicated that endogenously generated adenosine, through activation of PMN adenosine A2A and A2B receptors, functions as an antiadhesive signal for PMN binding to microvascular endothelia. Intravascular nucleotides released by inflammatory cells undergo phosphohydrolysis via hypoxia-induced CD39 ectoapyrase (CD39 converts adenosine triphosphate/adenosine diphosphate [ATP/ADP] to adenosine monophosphate [AMP]) and CD73 ecto-5'-nucleotidase (CD73 converts AMP to adenosine). Extensions of our in vitro findings using cd39- and cd73-null animals revealed that extracellular adenosine produced through adenine nucleotide metabolism during hypoxia is a potent anti-inflammatory signal for PMNs in vivo. These findings identify CD39 and CD73 as critical control points for endogenous adenosine generation and implicate this pathway as an innate mechanism to attenuate excessive tissue PMN accumulation. (Blood. 2004;104:3986-3992)
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