IMMUNOLOGICAL ACTIVATION OF HEPATIC MACROPHAGES IN SEPTIC RATS - A POSSIBLE MECHANISM OF SEPSIS-ASSOCIATED LIVER-INJURY

To investigate the pathogenesis of liver dysfunction accompanying intr a-abdominal sepsis, we used rats with cecal ligation and punctures (CL P) and examined the expression of the inflammatory cytokines IL-1-alph a, IL-1-beta, and TNF-alpha, as well as the expression of a cell adhes ion 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 s ignificantly 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 I hour after CLP, increasing to the maxi mal level 3 hours after CLP, whereas IL-1-beta mRNA was induced gradua lly, reaching a peak 6 hours after CLP. ICAM-1 mRNA reached a peak 3 h ours after CLP. Induction of TNF-alpha mRNA was not detected by the pr esent Northern blot analysis. Seventy-two hours after CLP, the proport ions of hepatic macrophages expressing la antigens and IL-2R were incr eased significantly, as revealed by the flow cytometric analysis. In c onclusion, 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 immunomodu latory surface molecules. Further, we demonstrated the sequential indu ction of the mRNA of the various inflammatory cytokines and ICAM-1. Th ese findings strengthen the notion that these cytokines are relevant t o the pathogenesis of liver injury associated with sepsis.