title: The impact of resuscitated fecal peritonitis on the expression of the hepatic bile salt transporters in a porcine model.
abstract: Sepsis is often associated with cholestatic liver dysfunction caused by changes in the expression profile of hepatic bile salt transporters. However, in rodent endotoxin models, the role of ischemic hepatitis caused by liver hypoperfusion cannot be delineated. We hypothesized that hepatocytes change their expression pattern of bile salt transporters during early severe sepsis despite adequate resuscitation. Fifteen anesthetized and instrumented pigs were randomized to either fecal peritonitis (n = 8) or control (n = 7). Resuscitation was performed by hydroxyethyl starch and norepinephrine infusion. Hemodynamic parameters and markers of cholestatic and ischemic hepatic dysfunction were recorded. At baseline and after 21 h, messenger RNA (mRNA) and protein expression of bile salt transporters was determined by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively, on in vivo liver biopsies. All resuscitated septic pigs developed a normotensive hyperdynamic circulation with increased portal flow. After 21 h of peritonitis, no signs of biochemical or histological cholestasis were present. Na-taurocholate cotransporting polypeptide and bile salt export pump mRNA were downregulated by 83% (P = 0.001) and 67% (P = 0.001), respectively, in comparison with controls, whereas multidrug resistance-associated protein 4 (MRP4) mRNA was upregulated by 85% (P = 0.02). Bile salt export pump and MRP2 staining were downregulated in septic pigs. During early porcine fluid-resuscitated sepsis, hepatic basolateral influx (Na-taurocholate cotransporting polypeptide) and canalicular efflux (bile salt export pump) of bile salts were downregulated without hemodynamic signs of hepatic hypoperfusion or biochemical signs of cholestasis. In parallel, the basolateral escape transport (MRP4) was markedly upregulated, possibly as an early adaptive response to counteract hepatocellular accumulation of toxic bile acids.
authors.affiliation: Medical Intensive Care Unit, University Hospitals of the Katholieke Universiteit Leuven, Leuven, Belgium. joost.wauters@med.kuleuven.be
authors.forename: Joost
authors.initials: J
authors.lastname: Wauters
authors.forename: Dieter
authors.initials: D
authors.lastname: Mesotten
authors.forename: Kenny
authors.initials: K
authors.lastname: Van Zwam
authors.forename: Jos
authors.initials: J
authors.lastname: van Pelt
authors.forename: Steven
authors.initials: S
authors.lastname: Thiessen
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Dieudonné
authors.forename: Sara
authors.initials: S
authors.lastname: Vander Borght
authors.forename: Greet
authors.initials: G
authors.lastname: Van den Berghe
authors.forename: Alexander
authors.initials: A
authors.lastname: Wilmer
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D005243:Feces; D005260:Female; D005786:Gene Expression Regulation; D006439:Hemodynamics; D006895:Hydroxyethyl Starch Derivatives / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008102:Liver Circulation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000235:genetics; D009638:Norepinephrine / Q000627:therapeutic use*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000096:biosynthesis* / Q000235:genetics; D010538:Peritonitis / Q000150:complications / Q000378:metabolism* / Q000628:therapy; D012333:RNA, Messenger / Q000096:biosynthesis; D011897:Random Allocation; D012151:Resuscitation; D018805:Sepsis / Q000209:etiology / Q000378:metabolism* / Q000628:therapy; D034421:Sus scrofa; D013552:Swine; D027981:Symporters / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D006895:Hydroxyethyl Starch Derivatives; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009638:Norepinephrine; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D027981:Symporters; C071908:sodium-bile acid cotransporter