Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism.
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 A(2A) and A(2B) 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.
Eltzschig
Holger K
HK
Brigham and Women's Hospital, Harvard Medical School, Thorn Building 704, 75 Francis Street, Boston, MA 02115, USA.
Thompson
Linda F
LF
Karhausen
Jorn
J
Cotta
Richard J
RJ
Ibla
Juan C
JC
Robson
Simon C
SC
Colgan
Sean P
SP
D000241:Adenosine / Q000097:blood*; D000251:Adenosine Triphosphatases / Q000097:blood / Q000235:genetics; D015703:Antigens, CD / Q000097:blood / Q000235:genetics; D001081:Apyrase; D001483:Base Sequence; D002448:Cell Adhesion; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D008833:Microcirculation; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D009711:Nucleotides / Q000378:metabolism*
D015703:Antigens, CD; D017931:DNA Primers; D009711:Nucleotides; D000251:Adenosine Triphosphatases; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine