title: Hypoxia of the growing liver accelerates regeneration.
abstract: After portal vein ligation of 1 side of the liver, the other side regenerates at a slow rate. This slow growth may be accelerated to rapid growth by adding a transection between the 2 sides, i.e., performing portal vein ligation and parenchymal transection. We found that in patients undergoing portal vein ligation and parenchymal transection, portal vein hyperflow in the regenerating liver causes a significant reduction of arterial flow due to the hepatic arterial buffer response. We postulated that the reduction of arterial flow induces hypoxia in the regenerating liver and used a rat model to assess hypoxia and its impact on kinetic growth.
  
  
  
  A rat model of rapid (portal vein ligation and parenchymal transection) and slow regeneration (portal vein ligation) was established. Portal vein flow and pressure data were collected. Liver regeneration was assessed in rats using computed tomography, proliferation with Ki-67, and hypoxia with pimonidazole and HIF-1α staining.
  
  
  
  The rat model confirmed acceleration of regeneration in portal vein ligation and parenchymal transection as well as the portal vein hyperflow seen in patients. Additionally, tissue hypoxia was observed after portal vein ligation and parenchymal transection, while little hypoxia staining was detected after portal vein ligation. To determine if hypoxia is a consequence or an inciting stimulus of rapid liver regeneration, we used a prolyl-hydroxylase blocker to activate hypoxia signaling pathways in the slow model. This clearly accelerated slow to rapid liver regeneration. Inversely, abrogation of hypoxia led to a blunting of rapid growth to slow growth. The topical application of prolyl-hydroxylase inhibitors on livers in rats induced spontaneous areas of regeneration.
  
  
  
  This study shows that pharmacologically induced hypoxic signaling accelerates liver regeneration similar to portal vein ligation and parenchymal transection. Hypoxia is likely an accelerator of liver regeneration. Also, prolyl-hydroxylase inhibitors may be used to enhance liver regeneration pharmaceutically.
authors.affiliation: Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; Division of Transplant Surgery, Department of Surgery, Rush University Medical Center, Chicago, IL; Department of Surgery, Cantonal Hospital Winterthur, Zürich, Switzerland. Electronic address: erik.schadde@uzh.ch.
authors.forename: Erik
authors.initials: E
authors.lastname: Schadde
authors.affiliation: Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: Christopher
authors.initials: C
authors.lastname: Tsatsaris
authors.affiliation: Division of Hepatology, Department of Gastroenterology, Duke University, Durham, NC.
authors.forename: Marzena
authors.initials: M
authors.lastname: Swiderska-Syn
authors.affiliation: Department of Surgery, Cantonal Hospital Winterthur, Zürich, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Breitenstein
authors.affiliation: Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; Institute of Anesthesiology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Urner
authors.affiliation: Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: Roman
authors.initials: R
authors.lastname: Schimmer
authors.affiliation: Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: Christa
authors.initials: C
authors.lastname: Booy
authors.affiliation: Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: Birgit Roth
authors.initials: BR
authors.lastname: Z'graggen
authors.affiliation: Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland.
authors.forename: Roland H
authors.initials: RH
authors.lastname: Wenger
authors.affiliation: Institute of Anesthesiology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Donat R
authors.initials: DR
authors.lastname: Spahn
authors.affiliation: Division of Transplant Surgery, Department of Surgery, Rush University Medical Center, Chicago, IL.
authors.forename: Martin
authors.initials: M
authors.lastname: Hertl
authors.affiliation: Division of Transplantation, Department of Surgery, Duke University, Durham, NC.
authors.forename: Stuart
authors.initials: S
authors.lastname: Knechtle
authors.affiliation: Division of Hepatology, Department of Gastroenterology, Duke University, Durham, NC.
authors.forename: Ann Mae
authors.initials: AM
authors.lastname: Diehl
authors.affiliation: Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; Institute of Anesthesiology, University Hospital Zürich, Zürich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Schläpfer
authors.affiliation: Institute of Physiology, Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland; Institute of Anesthesiology, University Hospital Zürich, Zürich, Switzerland; Department of Anesthesiology, University of Illinois Chicago, Chicago, IL.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Beck-Schimmer
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D006498:Hepatectomy; D008026:Ligation; D008099:Liver / Q000098:blood supply* / Q000473:pathology*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D011169:Portal Vein; D051381:Rats; D017208:Rats, Wistar