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.

Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis

“…Our results show that MPO activity and pro-inflammatory cytokine TNF-α production were correlated with the development of colonic inflammation and moreover curcumin administration was able to diminish both parameters. These findings are supported by previous in vivo and in vitro experiments where curcumin has been shown to reduce the levels of these inflammatory mediators [9,10,28,29].…”

Effect of Vitamin E Supplementation on Intestinal Barrier Function in Rats Exposed to High Altitude Hypoxia Environment

“…NF-κB exists as a trimer of p65, p50, and a distinct lκB subunit. Activated NF-κB migrates to the nucleus for binding to DNA control elements and induces via mRNA the expression of genes encoding large number of cytokines [46]. Locally, these molecules can lead to apoptosis of intestinal mucosal epithelial cells and damage the tissues and organs of the intestinal tract.…”

N‐ACETYLCYSTEINE IMPROVES INTESTINAL BARRIER IN PARTIALLY HEPATECTOMIZED RATS

“…Weber‐Mzell et al in accordance with this suggestion, suggested that the expression of cytokines like tumour necrosis factor‐α, interleukin (IL)‐2, IL‐8 and ICAM‐1 occurs with the activation of NF‐κB following the generation of ROS from the enterocytes by the way of xanthine oxidase. These cytokines disrupt the tight junctions and cause translocation of bacteria through these loosened passages 26 …”

“…These cytokines disrupt the tight junctions and cause translocation of bacteria through these loosened passages. 26 Malondialdehyte is a good indicator of oxidative injury as an end-product of lipid peroxidation. In the present study there was a minimal, but not significant increase in MDA values of the intestinal wall of sham groups when compared with the control group.…”