Liver regeneration Feb 9 2005 The legend of Prometheus Partial Hepatectomy Important model for studying cellular regeneration Higgins and Anderson 1931 Hundreds of studies have now addressed the control and consequences of cellular regeneration Simple surgical procedure in which 1 or more hepatic lobes are removed without damage to the remaining lobes Partial HPx cellular events The residual lobes first grow by hyperplasia and then by hypertrophy to match the mass of the removed lobes All of the existing mature cell types composing the liver regenerate Nearly all of the parenchymal cells in the remaining liver lobes participate in 1 or 2 proliferative cycles Within 7 10 days liver mass is restored Partial HPx pathogenesis Regeneration of the liver is a pathophysiological process Essentially a process of compensatory hyperplasia The increase in liver volume mass does not restore original macroanatomy Partial HPx rat model Most of what is known is based on 2 3 HPx in rats Process is divided into Priming phase in which cell acquire an enhanced capacity to proliferate Proliferation phase Termination phase Partial HPx still unknown Division of mature liver cells or stem cell proliferation Triggered by increase release of growth factors or decrease in concentration of circulating inhibitors Mechanisms responsible for memory of liver mass and precise termination of liver regeneration Partial HPx cell cycle entry At the time of HPx virtually all hepatocytes are in G0 After HPx all hepatocytes synchronously enter the cell cycle Maximal DNA synthesis occurs 24 hours after HPx Chemical injury CCl4 SER CCl3 Microsomal polyenoic fatty acid Lipid Radicals O2 Membrane Damage to RER LIPID PEROXIDATION Autocatalytic spread along microsomal membrane Release of Products of Lipid Peroxidation Damage to Plasma Membrane Polysome Detachment Permeability to Na H2O Ca2 Apoprotein Synthesis Cell Swelling Massive Influx of Ca2 Fatty Liver Inactivation of Mitochondria Cell Enzymes and Denaturation of Proteins Figure by MIT OCW Regeneration after liver injury Many toxins can cause liver damage necrosis and inflammation Hepatotoxic models are Easier to perform More clinically relevant Less reproducible Carbon tetrachloride CCl4 Classical hepatotoxin Induces liver injury by metabolites arising from P450 dependent breakdown First step is formation of reactive trichloromethyl radicals Trigger lipid peroxidation CCl4 regeneration Acute reversible liver injury following a single oral intraperitoneal or subcutaneous dose In mice 22 28 g single i p injection 0 1 ml kg diluted in corn oil Can enhance hepatotoxicity by simultaneous administration of phenobarbital Acetaminophen Frequent cause of acute liver failure Normally undergoes biotransformation in the liver by a combination of glucuronidation and sulphation After overdose these pathways are overwhelmed and P450 dependent metabolism takes place Formation of N acetyl benzoquinoneimine Central Vein Portal Tracts triads Portal Tract Limiting Plate Periportal 6 8 cells Figure by MIT OCW Centrilobular 8 10 cells GS 1 3 cells Mechanisms of apoptosis Figure removed for copyright reasons Source Figure 1 28 in RC Kumar V A K Abbas and N Fausto Robbins and Cotran Pathologic Basis of Disease Philadelphia PA Elsevier 2005 ISBN 0721601871 Extrinsic pathway of apoptosis Figure removed for copyright reasons Source Figure 1 29 in RC Intrinsic pathway of apoptosis Figure removed for copyright reasons Source Figure 1 30 in RC Ischemic cell injury Irreversible Injury Cell death Reversible Injury Membrane injury Ischemia Mitochondria Oxidative phosphorylation Na pump Cellular swelling Loss of microvilli Blebs ER swelling Myelin figures Influx of Ca2 H2O and Na Efflux of K Intracellular release and activation of lysosomal enzymes Glycolysis Glycogen Other effects Detachment of ribosomes Leakage of enzymes CK LDH Ca2 influx Clumping of nuclear chromatin pH ATP Loss of phospholipids Cytoskeletal alterations Free radicals Lipid breakdown Others Protein synthesis Lipid deposition Figure by MIT OCW Basophilia RNP Nuclear changes Protein digestion