Conclusion: These

findings Everolimus supplier implicate ENT1 in liver protection from ischemia and reperfusion injury and suggest ENT inhibitors may be of benefit in the prevention or treatment of ischemic liver injury. (Hepatology 2013;58:1766–1778) Ischemia and reperfusion is a pathologic condition characterized by an initial restriction of blood supply to an organ, followed by the subsequent restoration of perfusion and concomitant reoxygenation.[1, 2] In its classic manifestation, occlusion of the arterial blood supply is caused by an embolus and results in a severe imbalance of metabolic supply and demand causing tissue hypoxia. In the second stage of the disease, blood flow is rapidly restored. Somewhat surprisingly, the restoration of blood flow along with reoxygenation is frequently associated with an exacerbation of tissue injury and a profound inflammatory response Selleckchem Torin 1 (so-called reperfusion injury).[3] While ischemia and reperfusion contribute significantly to a wide range of pathologies, its functional contribution during liver surgery is particularly severe. For example, ischemia and

reperfusion is a frequent cause of acute liver failure during orthotopic liver transplantation. Similarly, ischemia and reperfusion selleck compound injury can contribute to immunologic consequences during human liver transplantation, as it is implicated in early rejection of the transplanted liver graft or the recurrence of hepatitis C in patients undergoing liver transplantation for the treatment of chronic hepatitis. Moreover, treatment modalities that would prevent hepatic ischemia and reperfusion injury are very limited and studies that aim to identify novel therapeutic approaches for hepatic ischemia and reperfusion are an area of intense investigation.[4, 5] Previous studies had shown that ischemia and reperfusion is associated with increased adenosine production from its precursor molecules—particularly

the nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP).[1, 6] Furthermore, it has been shown that activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A regulates local inflammation and prevents hepatocyte death.[7] Extracellular adenosine can signal through four distinct adenosine receptors (ARs), Adora1, Adora2a, Adora2b, or Adora3.[1] Studies of hepatic ischemia and reperfusion had shown a functional role for extracellular adenosine production,[8, 9] and signaling events through ARs—such as Adora2a[10] and Adora2b[11]—in liver protection from ischemia.