Downregulation of E. coli-induced TNF-alpha expression in perfused liver by hypoxia-reoxygenation.
We tested the hypothesis that reducing the hepatic O2 supply by 30 min of constant-flow hypoxia (PO2, approximately 45 Torr) following gram-negative bacteremia downregulates tumor necrosis factor-alpha (TNF-alpha) in buffer-perfused rat lives (total n = 44). Eight groups were studied after intraportal 10(9) viable E. coli serotype 055:B5 (EC) or 0.9% NaCl (NS) at t = 0:1) normoxic EC; 2) normoxic NS controls; 3) EC+hypoxia (H)-reoxygenation (R) in which H began 30 min after EC followed by 120 min of R; and 4) NS+H/R. To assess the role of cyclooxygenase vs. xanthine oxidase activation, the effects of 10(-5) M indomethacin (Indo) in 5) Indo+EC+H/R and 6) Indo+NS+H/R were compared with allopurinol (Allo) in 7) Allo+EC+H/R and 8) Allo+NS+H/R groups. Bacterial clearance, bioactive and antigenic TNF-alpha, and hepatic O2 uptake and performance were serially assessed, as was prostaglandin (PG) E2 at baseline and peak hypoxia in EC-challenged groups. Intrahepatic bacterial killing and TNF-alpha mRNA were determined at t = 180 min. Bioactive venous TNF-alpha did not increase in normoxic NS controls (6 +/- 3 U/ml at t = 180 min; mean +/- SE), whereas levels rose in NS4H/R by 180 min (111 +/- 34 U/ml; P < 0.01) without increases in TNF-alpha mRNA. In contrast, EC-induced increases in TNF-alpha transcripts during normoxia were attenuated in EC+H/R, as were protein levels (57 +/- 20 U/ml; P < 0.05), despite similar bacterial clearance. Neither Indo-mediated reductions in PGE2 nor allopurinol increased TNF-alpha after EC+H/R.(ABSTRACT TRUNCATED AT 250 WORDS)
Wibbenmeyer
L A
LA
Department of Surgery, Sant Louis University Health Sciences Center, Missouri.
Lechner
A J
AJ
Munoz
C F
CF
Matuschak
G M
GM
D000818:Animals; D016470:Bacteremia / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D004927:Escherichia coli Infections / Q000378:metabolism* / Q000382:microbiology; D000860:Hypoxia / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010100:Oxygen / Q000494:pharmacology*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors
D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D014969:Xanthine Oxidase; D010100:Oxygen