Role of Kupffer Cells in Vasoregulatory Gene Expression During Endotoxemia

Abstract

Although hepatic microcirculatory dysfunction occurs during endotoxemia, the mechanism responsible for this remains unclear. Since Kupffer cells provide signals that regulate hepatic response in inflammation, this study was designed to investigate the role of Kupffer cells in the imbalance in the expression of vasoactive mediators. Endotoxemia was induced by intraperitoneal E coli endotoxin (LPS, 1 mg/kg body weight). Kupffer cells were inactivated with gadolinium chloride (GdCl(3), 7.5 mg/kg body weight, intravenously) 2 days prior to LPS exposure. Liver samples were taken 6 h following LPS exposure for RT-PCR analysis of mRNA for genes of interest: endothelin (ET-1), its receptors ET(A) and ET(B), inducible nitric oxide synthase (iNOS), heme oxygenase (HO-1), and tumor necrosis factor-alpha (TNF-alpha). mRNA levels for iNOS and TNF-alpha were significantly increased 31.8-fold and 26.7-fold in LIPS-treated animals, respectively. This increase was markedly attenuated by GdCl(3), HO-1 expression significantly increased in LPS-treated animals, with no significant difference between saline and GdCl3 groups. ET-1 was increased by LIDS. mRNA levels for ETA receptor showed no change, whereas ETB transcripts increased in LPS-treated animals. The increase in ETB transcripts was potentiated by GdCl(3). We conclude that activation of Kupffer cells plays an important role in the imbalanced hepatic vasoregulatory gene expression induced by endotoxin.