Inhibition of IKKβ in Enterocytes Exacerbates Sepsis-Induced Intestinal Injury and Worsens Mortality

Abstract

Objective NF-kB is a critical regulator of cell survival genes and the host inflammatory response. The purpose of this study was to investigate the role of enterocyte-specific NF-kB in sepsis through selective ablation of IkB kinase (IKK)-ß. Design Prospective, randomized, controlled study. Setting Animal laboratories in university medical centers. Subjects and Interventions Mice lacking functional NF-kB in their intestinal epithelium (Vil-Cre/Ikkßf/Δ) and wild type (WT) mice were subjected to sham laparotomy or cecal ligation and puncture (CLP). Animals were sacrified at 24 hours or followed seven days for survival. Measurements and Main Results Septic WT mice had decreased villus length compared to sham mice while villus atrophy was further exacerbated in septic Vil-Cre/Ikkßf/Δ mice. Sepsis induced an increase in intestinal epithelial apoptosis compared to sham mice which was further exacerbated in Vil-Cre/Ikkßf/Δ mice. Sepsis induced intestinal hyperpermeability in WT mice compared to sham mice, which was further exacerbated in septic Vil-Cre/Ikkßf/Δ mice. This was associated with increased intestinal expression of claudin-2 in septic WT mice, which was further increased in septic Vil-Cre/Ikkßf/Δ mice. Both, pro-inflammatory and anti-inflammatory cytokines were increased in serum following CLP, and IL-10 and MCP-1 levels were higher in septic Vil-Cre/Ikkßf/Δ mice than septic WT mice. All septic mice were bacteremic, but no differences in bacterial load were identified between WT and Vil-Cre/Ikkßf/Δ mice. To determine the functional significance of these results, animals were followed for survival. Septic WT mice had lower mortality than septic Vil-Cre/Ikkßf/Δ mice (47% vs. 80%, p<0.05). Anti-TNF administration decreased intestinal apoptosis, permeability and mortality in WT septic mice and a similar improvement in intestinal integrity and survival were seen when anti-TNF was given to Vil-Cre/Ikkßf/Δ mice. Conclusions Enterocyte-specific NF-kB has a beneficial role in sepsis by partially preventing sepsis-induced increases in apoptosis and permeability, which are associated with worsening mortality.

Endothelium-Derived 5-Methoxytryptophan Is a Circulating Anti-Inflammatory Molecule That Blocks Systemic Inflammation

“…It has been shown that the inhibition of NF-κB is significantly correlated with improvement of survival from endotoxin shock and sepsis. 38,39 Our results further demonstrate that 5-MTP blocks NF-κB by interrupting p38 MAPK signaling pathway. Although signaling kinases such as p38 MAPK and ERK1/2 are activated and involved in TLRmediated responses, 17,18,40 5-MTP selectively suppresses p38 but not ERK1/2 activation.…”

Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis

“…TSLP has been shown to induce signal transducer and activator of transcription (STAT) 1, STAT3, STAT4, STAT5, and STAT6 phosphorylation in human DCs, whereas it only activates STAT5 in mouse DCs (37,39 The down-regulatory effects of TSLP on inflammation may not be limited to its direct effects on myeloid cell function. Recent studies indicate that injury is associated with increased inflammation and worsens mortality in septic mice that do not express the transcription factor, NF-kB, in their intestinal epithelium (41). Injury is also one of the main triggers for TSLP production by epithelial cells (10), which requires the activation of the NF-kB signaling pathway (42).…”

The intestinal microenvironment in sepsis

“…A complementary approach demonstrating the importance of intestinal epithelial apoptosis and permeability involved transgenic mice lacking functional Nuclear Factor kappa B (NFkB) in their intestinal epithelium (75). When sepsis in induced in these animals via CLP, both intestinal epithelial apoptosis and permeability are greater than is seen in wild type septic animals, associated with an increase in claudin 2 levels.…”