The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

Abstract

Extracellular nucleotides (e.g. ATP, UTP, ADP) are released by activated endothelium, leukocytes and platelets within the injured vasculature and bind specific cell-surface type-2 purinergic (P2) receptors. This process drives vascular inflammation and thrombosis within grafted organs. Importantly, there are also vascular ectonucleotidases i.e. ectoenzymes that hydrolyze extracellular nucleotides in the blood to generate nucleosides (viz. adenosine). Endothelial cell NTPDase1/CD39 has been shown to critically modulate levels of circulating nucleotides. This process tends to limit the activation of platelet and leukocyte expressed P2 receptors and also generates adenosine to reverse inflammatory events. This vascular protective CD39 activity is rapidly inhibited by oxidative reactions, such as is observed with liver ischemia reperfusion injury. In this review, we chiefly address the impact of these signaling cascades following liver transplantation. Interestingly, the hepatic vasculature, hepatocytes and all non-parenchymal cell types express several components co-ordinating the purinergic signaling response. With hepatic and vascular dysfunction, we note heightened P2- expression and alterations in ectonucleotidase expression and function that may predispose to progression of disease. In addition to documented impacts upon the vasculature during engraftment, extracellular nucleotides also have direct influences upon liver function and bile flow (both under physiological and pathological states). We have recently shown that alterations in purinergic signaling mediated by altered CD39 expression have major impacts upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses. Future clinical applications in transplantation might involve new therapeutic modalities using soluble recombinant forms of CD39, altering expression of this ectonucleotidase by drugs and/or using small molecules to inhibit deleterious P2-mediated signaling while augmenting beneficial adenosine-mediated effects within the transplanted liver.

Figure 1

Principles of purinergic signaling in the hepatic microenvironment. Nucleotides are released from parenchymal cells, non-parenchymal cells and platelets. These nucleotides then activate P2 receptors or are hydrolyzed by NTPDases and 5’nucleotidase to adenosine, which activates P1 receptors.

Figure 2

P2 receptor expression by hepatic sinusoidal endothelial cells. High levels of mRNA for P2Y1, P2Y2, P2X4 and P2X7 are noted. The expression of P2Y6 is weak and no signals for P2Y4, P2X1 and P2X2 are noted.

Figure 3

Immunohistochemical patterns of expression of CD39 in donor human liver. Endothelial cells of the portal vein (pv), hepatic artery (ha) and Kupffer cells strongly express CD39. Quiescent sinusoidal endothelial cells and bile duct (bd) epithelia do not stain for CD39.