Cytokine and acute phase protein mRNA expression in liver tissue from pigs with severe sepsis caused by intravenous inoculation of Staphylococcus aureus

The aim was to substantiate previous findings of hepatic dysfunction in a porcine model of Staphylococcus aureus induced severe sepsis. Nine pigs were inoculated intravenously once or twice with 108S. aureus per kilogram body weight and killed 12, 24 and 48 h later. Three pigs served as controls. Blood was sampled for bacteriology, haematology and clinical pathology. Tissues were collected at necropsy for bacteriology, gene expression analysis and histology. Bacterial counts in blood remained low, decreased in the lungs, liver and spleen, but increased in bone. All infected pigs developed sepsis characterized by fever, neutrophilia, increased serum levels of C-reactive protein (CRP) and interleukin (IL)-6, and decreased levels of serum iron. CRP and IL-6 serum levels peaked at 36 h. Serum IL-1β and tumour necrosis factor-α (TNFα) did not change. Serum aspartate aminotransferase (AST) and bilirubin were elevated at 36 and 48 h. Microabscesses were found in the livers from pigs killed at 12 h only. The livers from pigs killed at 48 h also showed light, diffuse fibrin exudation (vascular leakage). Real-time PCR showed a decreased hepatic expression of mRNA coding for albumin and increased hepatic expression of IL-6, IL-8, IL-1β, and CRP. N o increase could be detected in the IL-1α or TNFα liver-mRNA levels. IL-6, IL-8 and IL-1β expression peaked at 24 hours (2-5 fold compared to the control group). In conclusion, the increased liver cytokine mRNA levels indicate a local hepatic, non-infectious inflammatory response, and supports evidence of liver dysfunction indicated by increase in AST and bilirubin, and liver histopathology. Although hepatocyte IL-8 production has been proposed to indicate hepatocyte stress, the increased mRNA IL-8 levels, as the increase of the other cytokines, could have originated from cellular sources not constitutive to the liver. This warrants future examination of the liver by e.g. laser capture microdissection. Supported by grant no. 271-07-0417 from the Danish Medical Research Council