Liver
ischemia reperfusion injury is associated with both local damage to the hepatic vasculature and systemic inflammatory responses. CD39 is the dominant vascular endothelial cell ectonucleotidase and rapidly hydrolyses both
adenosine triphosphate (
ATP) and
adenosine diphosphate to
adenosine monophosphate. These biochemical properties, in tandem with 5'-nucleotidases, generate
adenosine and potentially illicit inflammatory vascular responses and
thrombosis. We have evaluated the role of CD39 in total hepatic
ischemia reperfusion injury (IRI). Wildtype mice, Cd39-hemizygous mice (+/-) and matched Cd39-null mice (-/-); (n = 25 per group) underwent 45 min of total
warm ischemia with full inflow occlusion necessitating partial
hepatectomy. Soluble
nucleoside triphosphate diphosphohydrolase (NTPDases) or
adenosine/
amrinone were administered to wildtype (n = 6) and Cd39-null mice (n = 6) in order to study protective effects in vivo. Parameters of liver injury, systemic
inflammation, hepatic
ATP determinations by P(31)-NMR and parameters of
lung injury were obtained. All wildtype mice survived up to 7 days with minimal biochemical disturbances and minor evidence for injury. In contrast, 64% of Cd39+/- and 84% of Cd39-null mice required
euthanasia or died within 4 h post-reperfusion with liver damage and systemic
inflammation associated with
hypercytokinemia. Hepatic
ATP depletion was pronounced in Cd39-null mice posthepatic IRI. Soluble NTPDase or
adenosine administration protected Cd39-deficient mice from acute
reperfusion injury. We conclude that CD39 is protective in hepatic IRI preventing local injury and systemic
inflammation in an
adenosine dependent manner. Our data indicate that vascular CD39 expression has an essential protective role in hepatic IRI.