ABSTRACT
BACKGROUND AND AIMS: Heparanase (HPSE) is an endo-ß-D-glucuronidase, which cleaves heparan sulfate in the extracellular matrix (ECM) and has pro-angiogenic and pro-proliferative properties. The aim of this investigation was to study the effect of HPSE on hepatocytes and endothelial cells (EC) during liver regeneration. METHODS: Following 70% hepatectomy (PHP), rats were injected daily with 1-50µg HPSE/rat. Liver samples were stained with H&E and anti-bromodeoxyuridine (BrdU) antibody. mRNAs of hepatocyte growth factor (HGF), stem cell factor, tumor necrosis factor (TNF)-α, interleukin(IL)-6, and cyclinD1 were tested by real-time qPCR. Matrix metalloproteinases (MMPs) were tested by gel zymography. RESULTS: Compared to the saline control, HPSE increased hepatocyte proliferation 24h, 48h and 72h after PHP, with the maximal effect found at 24h with 50µg HPSE (40.9±2.5% vs. 8.6±4.3%, p<0.01 for BrdU staining; 5.5±0.9% vs. 0.8±0.5%, p<0.05 for mitosis). Proliferation of the sinusoidal and the portal vein radical ECs was also increased (p<0.05). HPSE caused a twofold increase in cyclinD1 mRNA (p<0.05) and in pro-MMP-9 levels (p<0.05). HPSE at all doses also caused significant reductions of TNF-α mRNA (p<0.05) and IL-6 mRNA, and no change in HGF mRNA. CONCLUSIONS: HPSE enhances liver regeneration by inducing proliferation of hepatocytes and both sinusoidal and vascular ECs. Since the effect of HPSE on hepatocytes occurred earlier than that observed in ECs, this effect is not related to HPSE's effect on ECs. The mechanism of HPSE action is probably indirect and is mediated by HPSE-dependent ECM cleavage and the release of pre-existing enzymes.
Subject(s)
Cell Proliferation , Endothelial Cells/drug effects , Glucuronidase/pharmacology , Hepatectomy , Hepatocytes/drug effects , Animals , Cyclin D1/biosynthesis , Endothelial Cells/metabolism , Endothelial Cells/physiology , Hepatocyte Growth Factor/metabolism , Hepatocytes/metabolism , Hepatocytes/physiology , Interleukin-6/metabolism , Liver Regeneration/drug effects , Liver Regeneration/physiology , Male , Matrix Metalloproteinase 9/metabolism , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
This paper describes the rapid evolution of modern liver surgery, starting in the middle of the twentieth century. Claude Couinaud studied and described the segmental anatomy of the liver, Thomas Starzl performed the first liver transplantations, and Henri Bismuth introduced the concept of anatomical resections. Hepatic surgery has developed significantly since those early days. To date, innovative techniques are applied, using cutting-edge technologies: Intraoperative ultrasound, techniques of vascular exclusion of the liver, new devices for performing homeostasis and dissection, laparoscopy for resections, and new drugs that allow the resection of previously unresectable tumors. The next stage in liver surgery will probably be the implementation of a multidisciplinary holistic approach to the liver-diseased patient that will ensure the best and most efficient treatments in the future.
