COMPARATIVE STUDY
JOURNAL ARTICLE

The impact of resuscitated fecal peritonitis on the expression of the hepatic bile salt transporters in a porcine model

Joost Wauters, Dieter Mesotten, Kenny Van Zwam, Jos van Pelt, Steven Thiessen, Anne-Sophie Dieudonné, Sara Vander Borght, Greet Van den Berghe, Alexander Wilmer
Shock 2010, 34 (5): 508-16
20357697
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.

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