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 NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2010 June 25. Published in final edited form as:Front Biosci. ; 13: 2588-2603. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 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. KeywordsTransplantation; Liver; Purinergic Receptors; Bile; CD39; ecto-ATPase; Endothelium; Immunology; Metabolism; NTPDase; Platelet; Vasculature; Review INTRODUCTIONPurinergic signaling comprises release of extracellular nucleotides, stimulation of purinergic receptors and the modulation of nucleotide levels by ectoenzymes. Over the past decade, many advances have been made in the study of purinergic receptors and the regulation of extracellular nucleotide concentrations (1). It is now generally accepted that extracellular nucleotides (e.g. ATP, UTP, ADP), and the derivative nucleosides (e.g. adenosine from ATP), are released in a regulated manner by cells to provide the primary components for purinergic responses (2). Specific nucleo...

Immune cell regulation by autocrine purinergic signalling

“…Four families of ectonucleotidases that hydrolyze extracellular ATP have been identified in mammalian cells. These ectoenzymes include the ectonucleoside triphosphate diphosphohydrolase (ENTPD) family, the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) family, alkaline phosphatase and ecto-5’-nucleotidase (also known as CD73) 3, 18, 28 . The ENTPD family comprises seven different isoforms (ENTPD1-6 and ENTPD8) of which ENTPD1-3 and ENTPD8 are known to hydrolyze ATP or ADP to AMP with different substrate preferences.…”

“…The complex network of ectonucleotidases that regulates the ligand availability for P1 and P2 receptors in different tissues have a central role in defining immune responses in these tissues 7, 18 . ENTPD1 (CD39), which converts ATP to AMP, the precursor of adenosine and 5’-ectonuleotidase (CD73) that forms adenosine from AMP are particularly important for the balance between the pro- and anti-inflammatory effects of released cellular ATP 28 . This can be observed in ENTPD1-deficient mice that develop more severe injury-induced inflammation than wild-type mice, apparently due to the reduced ATP hydrolysis, adenosine formation and A2a receptor activation 102 .…”

P2Y 2 Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling

“…However, several P2 receptors were differentially expressed between fast- and slow-growing lines: P2Y1 , P2Y2 , and P2Y14 were significantly downregulated in S-hCPCs compared to F-hCPCs (0.031±0.015 fold change, P=0.012; 0.22±0.046 fold change, P=0.0112; and 0.058±0.014 fold change, P=0.0014, respectively) (Figure 2). P2Y 2 R was particularly intriguing based upon prior reports of involvement in regeneration using various experimental models 13–15, 23, 24 and in stem cells from diverse origins 18, 25 . Higher P2Y 2 R mRNA expression levels corresponded with faster hCPC growth rates indicated by shorter doubling times (R=0.7101, P=0.0369) (Online Figure IA).…”

“…P2Y 2 R is a potent stimulator of cell proliferation and migration 13–15, 32, 33 . Consistent with these findings, hCPC stimulation with P2Y 2 R agonist UTP for 24 hours significantly enhanced cell proliferation (1.56±0.073 fold change, P < 0.0001) (Figure 4C).…”

“…P2Y 2 R plays a central role in intracellular signaling by enabling extracellular ATP and UTP to promote regenerative responses in a variety of tissues. P2Y 2 R regulates corneal epithelia wound healing 13 and salivary gland reconstitution 14 by inducing cell migration, liver regeneration by promoting hepatocyte proliferation 15 , and reepithelialization following experimental colitis 16 and inflammatory bowel disease 17 . On the stem cell level, UTP is a potent stimulant of human hematopoietic stem cell (hHSC) migration 18 .…”