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FASEB J. 2008 Aug;22(8):2784-97. doi: 10.1096/fj.07-103911. Epub 2008 Mar 19.

Role of extracellular nucleotide phosphohydrolysis in intestinal ischemia-reperfusion injury.

Author information

1
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. melaniehar@googlemail.com

Abstract

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.

PMID:
18353866
PMCID:
PMC2493465
DOI:
10.1096/fj.07-103911
[Indexed for MEDLINE]
Free PMC Article
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