Brief hypoxic stress downregulates e. coli-induced il-1[alpha] and
il-1[beta] gene expression in perfused liver.
Matuschak, George M., Cheryl A. Johanns, Zhoumou Chen, Jeremy Gaynor,
and Andrew J. Lechner.
Division of Pulmonology, Department of Internal Medicine and
Department of Pharmacological and Physiological Science, Saint Louis
University Health Sciences Center, Saint Louis, Missouri and
Department of Critical Care Medicine, Saint John's Mercy Medical
Center, Saint Louis, Missouri
APStracts 3:0187R, 1996.
Hepatic cytokine gene expression is independently stimulated by
circulating microbial products and reductions in the cellular O2
supply. Although these stimuli occur sequentially following gram
-negative bacteremia, it is unknown whether their interplay augments
production of interleukin (IL)-1 by the liver. We studied the effects
of intraportal E. coli (EC) bacteremia and secondary constant-flow
hypoxia (PO2, _ 46 Torr for 30 min) on IL-1[alpha] and IL-1[beta]
gene expression in ex situ buffer-perfused rat livers over 180 min (n
= 67). At t = 0 normoxic EC and NS controls received 109 live EC
serotype 055:B5 or 0.9% NaCl (NS); in EC + H/R and NS + H/R livers
hypoxia (H) began 0.5 h after EC or NS, followed by 120 min of
reoxygenation (R). Portal and hepatic venous perfusates were serially
analyzed for bacterial cfu's, VO2, and aspartate aminotransferase
(AST). At t = 60 min (peak hypoxia) and t = 180 min, cDNAs for IL
-1[alpha] and IL-1[beta] were hybridized to whole-liver RNA and IL
-1[beta] protein levels in venous perfusates were assessed.
Intrahepatic levels of reduced glutathione (GSH) were measured as an
index of oxidative stress. Compared to normoxic EC, IL-1[alpha]
transcripts decreased at t = 180 min in EC + H/R livers (P <
0.0001) as did IL-1[beta] mRNA (P < 0.05) despite similar EC
clearance, GSH levels, post-hypoxic VO2, and AST release. Hepatic
secretion of IL-1[beta] likewise fell in EC + H/R vs. EC controls (P
< 0.005). Prostaglandin H synthase-2 (COX-2) message
accumulation was not enhanced by H/R and indomethacin did not reverse
H/R-mediated suppression of IL-1 production. In contrast, H/R-related
falls in EC-induced IL-1[beta] expression were reversed by
allopurinol or catalase. Thus, brief hypoxic stress of the liver
causing neither GSH depletion nor functional impairment downregulates
post-bacteremic IL-1 expression by a mechanism involving O2 radicals
but not cyclooxygenase metabolites.
Received 24 January 1996; accepted in final form 13 May 1996.
APS Manuscript Number R35-6.
Article publication pending Am. J. Physiol. (Regulatory Integrative
Comp. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 28 May 96