Absence of NO synthase type II expression in fetal liver from pregnant rats under septic shock conditions.

Abstract

Treatment of rats at 21 days' gestation with lipopolysaccharide (LPS) induced type II NO synthase (iNOS) expression in maternal liver but completely failed to elicit this response in the corresponding fetal tissue. The impaired response of fetal liver cannot be attributed to alterations in the sensitivity of this organ to LPS or to proinflammatory cytokines involved in iNOS expression (tumor necrosis factor alpha [TNF-alpha], interferon gamma [IFN-gamma]), because cultured fetal and adult hepatocytes similarly responded to these factors. Measurement of TNF-alpha and IFN-gamma levels in maternal and fetal serum showed a restricted permeability of placenta to these cytokines, results that were in agreement with the absence of iNOS expression in fetal liver. Moreover, analysis of nuclear factor kappaB, which is required for iNOS expression, showed an activation in nuclear extracts from livers of mothers under septic shock conditions but not in the corresponding fetal livers. However, cultured fetal hepatocytes prepared from mothers in septic shock displayed an anomalous pattern of iNOS expression, including a decreased response to LPS as well as a shift in sensitivity to TNF-alpha. These hepatocytes from LPS-treated mothers showed significant expression of iNOS in the absence of added stimuli. These results suggest that there is a priming of the fetal hepatocytes from mothers with septic shock. The characterization of the factors causing this priming process might provide additional clues understanding the control of iNOS expression in liver.