Immunologic activation of hepatic macrophages in septic rats: a possible mechanism of sepsis-associated liver injury.

To investigate the pathogenesis of liver dysfunction accompanying intra-abdominal sepsis, we used rats with cecal ligation and punctures (CLP) and examined the expression of the inflammatory cytokines IL-1-alpha, IL-1-beta, and TNF-alpha, as well as the expression of a cell adhesion molecule, ICAM-1, in the liver. We also examined the expression of Ia antigen and interleukin-2 receptor (IL-2R) on hepatic macrophages. Hepatic macrophages isolated from rats 24 hours after CLP exhibited significantly higher IL-1 and TNF activity than those from control rats. Hepatic macrophages isolated from rats 72 hours after CLP exhibited the maximal IL-1 and TNF activity. In the hepatic nonparenchymal cells, IL-1-alpha mRNA was induced 1 hour after CLP, increasing to the maximal level 3 hours after CLP, whereas IL-1-beta mRNA was induced gradually, reaching a peak 6 hours after CLP. ICAM-1 mRNA reached a peak 3 hours after CLP. Induction of TNF-alpha mRNA was not detected by the present Northern blot analysis. Seventy-two hours after CLP, the proportions of hepatic macrophages expressing Ia antigens and IL-2R were increased significantly, as revealed by the flow cytometric analysis. In conclusion, the present study showed that hepatic macrophages are in an activated state in sepsis as indicated by their increased production of inflammatory monokines and their increased expression of immunomodulatory surface molecules. Further, we demonstrated the sequential induction of the mRNA of the various inflammatory cytokines and ICAM-1. These findings strengthen the notion that these cytokines are relevant to the pathogenesis of liver injury associated with sepsis.