Purinergic regulation of hepatic inflammation and fibrosis and implications for liver surgery

Abstract

Liver cirrhosis, known to increase intra- and postoperative complications after hepatic resection, has always been considered a limiting factor by the liver surgeon. We analyzed the effect of hepatic inflow occlusion in minimally invasive liver resection in patients with HCC and cirrhosis, and found no increase in complications or liver failure. While clinical studies like these need to accompany the development of new surgical techniques to re-evaluate risks for individual patient groups, and keep cirrhotic patients from being excluded from optimal treatments, it is also crucial to better understand the underlying mechanisms regulating inflammation, fibrosis and cirrhosis. Chronic inflammation of the gut or the liver can result in fibrosis and increased risk of cancer. Inflammation and its resolution are finely regulated by a multitude of interconnected signaling pathways, including purinergic signaling by extracellular nucleotides and nucleosides. Extracellular ATP is known as a pro-inflammatory “danger signal” and adenosine as an immunoregulatory and pro-regenerative stimulus. The balance between ATP and adenosine is regulated by a group of cell-surface localized enzymes, ecto-nucleotide triphosphate diphosphohydrolases (ENTPD). CD39 (ENTPD1) is located on immune cells and leads to their immunoregulatory differentiation. ENTPD2 and 3 are similar enzymes that are expressed on portal fibroblasts and pericytes, and on endocrine and exocrine tissues, respectively. In the presented research project, different experimental models of acute and chronic, intestinal and hepatic inflammation were performed using mice with global or targeted deficiency for CD39, ENTPD2 or ENTPD3. These studies confirmed the central role that these ecto-enzymes play as a “switch” turning a local micro-milieu into an immunoregulatory environment. Macrophage-expressed CD39 was found to alleviate sclerosing cholangitis and biliary fibrosis. ENTPD2, while not affecting liver regeneration after partial hepatectomy, attenuates acute necrotic liver injury and liver fibrosis. ENTPD2 and, to a lesser extent ENTPD3 have protective properties in experimental colitis, most likely due to their expression on the enteric nervous system. Taken together, these findings expose the crucial role that CD39 and other ENTPD play through modulating purinergic signaling in creating an immunoregulatory microenvironment in gut and liver. These insights contribute to a better understanding of inflammation and anti-inflammatory medication in autoimmune diseases of liver and intestine.