The role of nuclear factor-kappa B in bacterial translocation in cholestatic rats.
Xanthinoxidase (XO) derived radical species are involved in bacterial translocation (BT) in cholestatic rats. The mechanism by which XO influences remains unclear. It has been shown recently that nuclear factor-kappa B (NF-kappaB), a ubiquitous transcription factor, can be activated by oxidative stress and thereby promote the process of BT. We investigated the effects of NF-kappaB inactivation on the incidence of BT in cholestatic rats. Sprague-Dawley rats were randomly assigned to one of eight groups: groups 1-4 were sham laparotomized rats either untreated (S1) or treated for 5 days with thalidomide (S2), curcumin (S3), or Inchin-ko (ICK; S4); groups 5-8 underwent common bile duct ligation (CBDL) for 5 days and were either untreated (C1) or treated with thalidomide (C2), curcumin (C3), or ICK (C4). After 5 days bacteriological cultures were performed from portal blood and V. cava, from the central mesenteric lymph node complex (MLN), spleen, and liver. The intensity of the activated NF-kappaB-subunit p65/p50 in the ileum mucosa was estimated by light microscopy and a scoring system from 1 to 20. Malondialdehyde (MDA) and myeloperoxidase activity (MPO) in the ileum were evaluated and expressed as U/g dry weight. Thalidomide and ICK reduced in CBDL-rats significantly the BT rate (63% vs. 18%, 63% vs. 30%, P<0.01). Enzyme estimations (MDA, MPO, and GSH) in sham operated animals showed no significant changes in the untreated groups compared with the treated groups. CBDL-rats pre-treatment with all three compounds caused a significant increase of MDA levels if groups were compared with the untreated C1-group (C1 31.6+/-7.7, C2 54.5+/-12.2, C3 53.3+/-11.2, and C4 47.2+/-9.4). GSH was reduced after the pre-treatment by all compounds but only significantly after curcumin pre-treatment (C1 vs. C3: 13.9+/-1.8 vs. 7.1+/-1.8; P<0.05). MPO estimations were significantly higher in the untreated C1-group if compared with groups C2, C3, and C4 (C1 1036.4+/-340.9, C2 709.9+/-125.9, C3 545.2+/-136.6, and C4 556.7+/-247.4; P<0.05). Thalidomide inhibited significantly the activation of NF-kappaB (C2 vs. C1: 6.0+/-4.5 vs. 12.7+/-5.3; P<0.01). Likewise, Curcumin and ICK suppressed NF-kappaB activation, but this did not reach significance in this experiment. NF-kappaB is involved in the process of BT in cholestatic rats and may be activated by XO derived ROS. We assume that the activated NF-kappaB initiates transcription of target genes inducing cytokine production, which in turn disrupts the tight junctions leading to BT from the intestinal lumen to the MLNs and circulation.
Weber-Mzell
D
D
Department of Paediatric Surgery, Medical University Graz, Graz, Austria. kinderchirurgie@meduni-graz.at
Zaupa
P
P
Petnehazy
T
T
Kobayashi
H
H
Schimpl
G
G
Feierl
G
G
Kotanko
P
P
Höllwarth
M
M
D000704:Analysis of Variance; D000818:Animals; D018988:Bacterial Translocation / Q000276:immunology; D002779:Cholestasis / Q000276:immunology / Q000382:microbiology* / Q000503:physiopathology*; D003474:Curcumin / Q000494:pharmacology; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D005978:Glutathione / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018375:Neutrophil Activation; D009195:Peroxidase / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013792:Thalidomide / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000378:metabolism*
D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C078038:inchinko-to; D008315:Malondialdehyde; D013792:Thalidomide; D009195:Peroxidase; D014969:Xanthine Oxidase; D005978:Glutathione; D003474:Curcumin