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.