title: Liver sinusoidal endothelial dysfunction after LPS administration: a role for inducible-nitric oxide synthase.
abstract: OBJECTIVE
  Sepsis is associated with microvascular dysfunction, which contributes to organ failure. Intrahepatic endothelial dysfunction occurs after exposure to lipopolysaccharide (LPS). The upregulation of inducible nitric oxide synthase (iNOS) has been shown to contribute to systemic vascular dysfunction after LPS administration. However, little is known about the effects of iNOS induction on the liver microcirculation. This study aimed at exploring, in the isolated rat liver perfusion model, the role of iNOS induction in liver microvascular dysfunction associated with endotoxemia.
  
  
  METHODS
  All experiments were conducted in male Wistar rats, after 24 h of LPS (5 mg/kg i.p.) or saline administration in the presence or absence of the iNOS inhibitor 1400 W (3 mg/kg i.p.), administered 3 and 23 h after LPS/saline injection. Liver microvascular function was assessed by isolated liver perfusion, followed by molecular studies and liver function tests.
  
  
  RESULTS
  At 24 h, LPS induced liver endothelial dysfunction, as shown by a decreased vasodilatory response to acetylcholine and decreased eNOS phosphorylation at Ser(1176). This was associated with liver injury, assessed by an increase in liver transaminases and decreased indocyanin green clearance, and increased nitrooxidative stress. iNOS inhibition prevented liver endothelial dysfunction, blunted the development of liver injury and attenuated LPS-induced nitrooxidative stress.
  
  
  CONCLUSIONS
  iNOS upregulation contributes to liver microvascular dysfunction in endotoxemia. This suggests that this mechanism deserves further exploration in studies addressing liver protection in the context of severe acute bacterial infection.
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università di Milano, Milano, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: La Mura
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Pasarín
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain.
authors.forename: Aina
authors.initials: A
authors.lastname: Rodriguez-Vilarrupla
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: García-Pagán
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Bosch
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain; Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Canada. Electronic address: juan.g.abraldes@ualberta.ca.
authors.forename: Juan G
authors.initials: JG
authors.lastname: Abraldes
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D055371:Acute Lung Injury / Q000139:chemically induced / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology*; D019446:Endotoxemia / Q000139:chemically induced / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D008070:Lipopolysaccharides; D052247:Nitric Oxide Synthase Type II; D000109:Acetylcholine
keywords: 1400W; Multi organ failure; Oxidative stress; Sepsis; Sinusoidal endothelial cells