Bidirectional effects of hepatic ischemia/reperfusion on e. coli
-induced tnf gene expression.
Epperly, Neil A., Andrew J. Lechner, Cheryl A. Johanns, Robert O.
Webster, and George M. Matuschak.
DIVISION OF PULMONOLOGY, DEPARTMENT OF INTERNAL MEDICINE,
DEPARTMENT OF PHARMACOLOGICAL AND PHYSIOLOGICAL SCIENCE, SAINT LOUIS
UNIVERSITY SCHOOL OF MEDICINE, SAINT LOUIS, MO 63110-0250 AND
DEPARTMENT OF CRITICAL CARE MEDICINE, SAINT JOHN'S MERCY MEDICAL
CENTER, SAINT LOUIS, MO
APStracts 2:0192R, 1995.
We tested the hypothesis that gram-negative bacteremia (GNB) and brief
(30 min) reductions in the hepatic O2 supply by low-flow ischemia
differentially modulate tumor necrosis factor-[alpha] (TNF) gene
expression owing to sequence-specific activation of cyclooxygenase
vs. complement (C) pathways. Buffer-perfused Sprague-Dawley rat
livers (n = 82) were studied over 180 min after intraportal 109 live
E. coli serotype 055:B5 (EC) or 0.9% NaCl (NS) at t = 0. Compared to
EC and NS controls receiving constant-flow perfusion, sequential GNB
and I/R were studied in EC + 30 I/R and NS + 30 I/R livers, in which
30 min of ischemia (I) beginning 0.5 h after EC or NS was followed by
120 min of reperfusion (R). This sequence was reversed in 30 I/R + EC
and 30 I/R + NS groups. Bacterial clearance, bioactive and antigenic
TNF, PGE2, hepatic O2 uptake and performance were serially assessed.
Venous TNF increased in EC controls to peak at 155 +/- 29 U/ml after
180 min (P < 0.001 vs. NS controls) as did hepatic TNF mRNA.
Both TNF transcripts and protein levels were markedly attenuated in
EC + 30 I/R (P < 0.001 vs. EC) despite equivalent EC clearance
by Kupffer cells. Indomethacin (10-5M) decreased I/R-induced PGE2
secretion and restored TNF to control levels. In contrast, TNF levels
in 30 I/R + EC perfusates exceeded those of EC + 30 I/R livers (P
< 0.05) and were indistinguishable from EC controls. Allopurinol
pretreatment but not heat inactivation of C or infusion of soluble
human complement receptor type 1 inhibited TNF production in 30 I/R +
EC organs. These results identify a novel sequence-dependent
interaction whereby hepatic O2 deprivation after GNB downregulates
TNF via generation of cyclooxygenase metabolites, while ischemia
preceding GNB increases cytokine expression via reactive O2 species
but not C activation.
Received 14 March 1995; accepted in final form 6 July 1995.
APS Manuscript Number R168-5.
Article publication pending Am. J. Physiol. (Regulatory Integrative
Comp. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 18 July 1995.