title: The role of nuclear factor-kappa B in bacterial translocation in cholestatic rats.
abstract: 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.
authors.affiliation: Department of Paediatric Surgery, Medical University Graz, Graz, Austria. kinderchirurgie@meduni-graz.at
authors.forename: D
authors.initials: D
authors.lastname: Weber-Mzell
authors.forename: P
authors.initials: P
authors.lastname: Zaupa
authors.forename: T
authors.initials: T
authors.lastname: Petnehazy
authors.forename: H
authors.initials: H
authors.lastname: Kobayashi
authors.forename: G
authors.initials: G
authors.lastname: Schimpl
authors.forename: G
authors.initials: G
authors.lastname: Feierl
authors.forename: P
authors.initials: P
authors.lastname: Kotanko
authors.forename: M
authors.initials: M
authors.lastname: Höllwarth
mesh_terms: 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*
chemical_list: 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