Endotoxin stimulates the gene expression of reactive oxygen
eliminating pathways in rat hepatic endothelial and kupffer cells in
a cell-specific fashion.
Spolarics, Zoltan.
Department of Anatomy, Cell Biology and Injury Sciences, New Jersey
Medical School, Newark, New Jersey
APStracts 2:0200G, 1995.
Reactive oxygen species (ROS) are mediators of cellular injury and
play a putative role in the onset of hepatic damage during
endotoxemia or sepsis. It has been suggested that the induction of
glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of the
hexose monophosphate shunt (HMS), may support the ROS-producing or
-eliminating pathways in hepatic endothelial and Kupffer cells during
endotoxemia. The aim of the study was to assess the in vivo LPS
-induced alterations in the rat gene expression of selected enzymes
which are in functional relationship with the HMS. We determined the
mRNA levels and activities of glucose transporter GLUT1, Mn- and
CuZn-dependent superoxide dismutases (Mn-SOD and CuZn-SOD), and Se
-dependent glutathione peroxidase (Se-GPX). Cellular extracts were
analyzed 7 or 22h after the injection of lipopolysaccharide (LPS,
E.Coli, 2 mg/kg, ip), or the injection of saline. Seven or 22h of LPS
exposure caused a 10-25 fold increase in GLUT1 mRNA levels in
endothelial and Kupffer cells. In parenchymal cells, GLUT1 mRNA
expression was low, and LPS caused no marked changes. The cellular
level of Mn-SOD mRNA was 20-40 times greater in all hepatic cells
from LPS-treated animals than in cells from control rats. LPS at 22h
increased Mn-SOD activity by 45% in endothelial cells, but caused no
significant changes in Kupffer or parenchymal cells. Message levels
and enzyme activities of CuZn-SOD and Se-GPX were significantly
elevated 22h after LPS injection in endothelial cells only. Thus, LPS
results in marked up-regulation of functionally related genes in
hepatic cells. In endothelial cells, the simultaneous up-regulation
of GLUT1, G6PD, Mn-, CuZn-SOD and Se-GPX may represent an important
mechanism for accelerated elimination of ROS released from activated
sinusoidal phagocytes. In Kupffer cells, the up-regulated GLUT1 and
G6PD together with the constitutively present superoxide dismutases
and lack of up-regulated Se-GPX suggest an elevated capacity to
produce O2- and H2O2 which is consistent with primed bacterial
killing.
Received 1 August 1995; accepted in final form 27 September 1995.
APS Manuscript Number G325-5.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 6 November 95