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Role of extracellular nucleotide phosphohydrolysis in intestinal ischemia-reperfusion injury

Melanie L. Hart^*,,1,2, Martina Henn^,1, David Köhler, Doris Kloor, Michel Mittelbronn, Iris C. Gorzolla, Gregory L. Stahl^* and Holger K. Eltzschig^,||,2

^* Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;

Department of Anesthesiology and Intensive Care Medicine, Center for Inflammation and Hypoxia, and

Institute of Brain Research, Tübingen University Hospital, Tübingen, Germany;

Department of Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany; and

^|| Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Health Science Center, Denver, Colorado, USA

² Correspondence: H.K.E., Mucosal Inflammation Program, Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Campus Box B113, Denver, CO 80262, USA. E-mail: holger.eltzschig{at}uchsc.edu; M.L.H., Department of Anesthesiology and Intensive Care Medicine, Center for Inflammation and Hypoxia, Tübingen University Hospital, Wilhelmstr. 56, Lothar Meyer Bau, 72074 Tübingen, Germany. E-mail: melaniehar{at}googlemail.com

Extracellular adenosine has been implicated as an innate antiinflammatory metabolite, particularly during conditions of limited oxygen availability such as ischemia. Because extracellular adenosine generation is primarily produced via phosphohydrolysis from its precursor molecule adenosine-monophosphate (AMP) through the enzyme ecto-5'-nucleotidase (CD73), we examined the contribution of CD73-dependent adenosine production in modulation of intestinal ischemia-reperfusion (IR) injury. Following transcriptional and translational profiling of intestinal tissue that revealed a prominent induction of murine CD73, we next determined the role of CD73 in protection against intestinal IR injury. Interestingly, pharmacological inhibition or targeted gene deletion of CD73 significantly enhanced not only local intestinal injury, but also secondary organ injury, following IR as measured by intestinal and lung myeloperoxidase, aspartate and alanine aminotransferase, interleukin (IL) -1, IL-6, and histological injury. To confirm the role of CD73 in intestinal adenosine production, we measured adenosine tissue levels and found that they were increased with IR injury. In contrast, CD73-deficient (cd73^–/–) mice had lower adenosine levels at baseline and no increase with IR injury. Finally, reconstitution of cd73^–/– mice or treatment of wild-type mice with soluble 5'-nucleotidase was associated with significantly lower levels of injury. These data reveal a previously unrecognized role of CD73 in attenuating intestinal IR-mediated injury.—Hart, M. L., Henn, M., Köhler, D., Kloor, D., Mittelbronn, M., Gorzolla, I. C., Stahl, G. L., Eltzschig, H. K. Role of extracellular nucleotide phosphohydrolysis in intestinal ischemia-reperfusion injury.

Key Words: CD73 • adenosine receptor • hypoxia • HIF • hypoxia-inducible factor