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Published on: December 18, 2010
Inhibition of IKKβ in enterocytes exacerbates sepsis-induced intestinal injury and worsens mortality
Jessica A Dominguez1, Alexandr J Samocha, Zhe Liang
11Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO. 2Department of Surgery, Washington University School of Medicine, St. Louis, MO. 3Emory Center for Critical Care and Department of Surgery, Emory Healthcare and Emory University School of Medicine, Atlanta, GA. 4Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
Objectives:
Nuclear factor-κB 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.
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/Ikkβ) and wild-type mice were subjected to sham laparotomy or cecal ligation and puncture. Animals were killed at 24 hours or followed 7 days for survival.
Measurements And Main Results:
Septic wild-type mice had decreased villus length compared with sham mice, whereas villus atrophy was further exacerbated in septic Vil-Cre/Ikkβ mice. Sepsis induced an increase in intestinal epithelial apoptosis compared with sham mice, which was further exacerbated in Vil-Cre/Ikkβ mice. Sepsis induced intestinal hyperpermeability in wild-type mice compared with sham mice, which was further exacerbated in septic Vil-Cre/Ikkβ mice. This was associated with increased intestinal expression of claudin-2 in septic wild-type mice, which was further increased in septic Vil-Cre/Ikkβ mice. Both, pro-inflammatory and anti-inflammatory cytokines were increased in serum following cecal ligation and puncture, and interleukin 10 and monocyte chemoattractant protein-1 levels were higher in septic Vil-Cre/Ikkβ mice than in septic wild-type mice. All septic mice were bacteremic, but no differences in bacterial load were identified between wild-type and Vil-Cre/Ikkβ mice. To determine the functional significance of these results, animals were followed for survival. Septic wild-type mice had lower mortality than septic Vil-Cre/Ikkβ mice (47% vs 80%, p<0.05). Antitumor necrosis factor administration decreased intestinal apoptosis, permeability, and mortality in wild-type septic mice, and a similar improvement in intestinal integrity and survival were seen when antitumor necrosis factor was given to Vil-Cre/Ikkβ 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.
Insights
Enterocyte-specific Nuclear factor-κB (NF-κB) plays a protective role in sepsis, mitigating intestinal damage and reducing mortality. Ablating NF-κB in intestinal cells worsens sepsis outcomes, highlighting its importance in host defense.
Area of Science:
- Gastroenterology
- Immunology
- Molecular Biology
Background:
- Nuclear factor-κB (NF-κB) is a key regulator of cell survival and inflammation.
- Understanding the role of specific NF-κB pathways in sepsis is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of enterocyte-specific NF-κB in sepsis.
- To determine the effects of selectively ablating IkB kinase (IKK) in intestinal cells on sepsis outcomes.
Main Methods:
- Prospective, randomized controlled study in university medical center animal laboratories.
- Mice with enterocyte-specific NF-κB deficiency (Vil-Cre/Ikkβ) and wild-type controls underwent cecal ligation and puncture (sepsis model) or sham surgery.
- Evaluated intestinal morphology, apoptosis, permeability, cytokine profiles, bacterial load, and survival rates.
Main Results:
- Septic mice exhibited villus atrophy, increased apoptosis, and hyperpermeability, which were significantly exacerbated in Vil-Cre/Ikkβ mice.
- Enterocyte-specific NF-κB deficiency led to higher levels of IL-10 and MCP-1.
- Mortality was significantly higher in septic Vil-Cre/Ikkβ mice (80%) compared to wild-type mice (47%).
- Anti-TNF therapy improved intestinal integrity and survival in both groups.
Conclusions:
- Enterocyte-specific NF-κB plays a beneficial role in sepsis.
- It partially prevents sepsis-induced apoptosis and hyperpermeability, thereby reducing mortality.
- Targeting NF-κB in intestinal cells may offer therapeutic potential for sepsis management.
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