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

• Type of Material: Article
• Authors: Jessica A. Dominguez, University of Colorado; Alexandr J. Samocha, Washington University St. Louis; Zhe Liang, Emory University; Eileen Burd, Emory University; Alton B Farris III, Emory University; Craig Coopersmith, Emory University
• Language: English
• Date: 2013-10-01
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.
• Final Published Version (URL): http://dx.doi.org/10.1097/CCM.0b013e31828a44ed
• Title of Journal or Parent Work: Critical Care Medicine
• ISSN: 0090-3493
• Volume: 41
• Issue: 10
• Start Page: E275
• End Page: E285
• Grant/Funding Information: This work was supported by funding from the National Institutes of Health (GM66202, GM072808, GM082008, P30 DK52574, Shock Society Early Career Investigator Fellowship).
• Keywords: CECAL LIGATION; gut; BARRIER DYSFUNCTION; permeability; TUMOR-NECROSIS-FACTOR; Life Sciences & Biomedicine; BINDING DOMAIN PEPTIDE; SYSTEMIC INFLAMMATION; apoptosis; NF-KAPPA-B; General & Internal Medicine; NF-kB; PSEUDOMONAS-AERUGINOSA PNEUMONIA; EPITHELIAL TIGHT JUNCTIONS; MULTIPLE-ORGAN-FAILURE; Science & Technology; sepsis; MURINE MODEL; tumor necrosis factor; Critical Care Medicine
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery

Abstract

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/Ikkβf/δ 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/Ikkβf/δ mice. Sepsis induced an increase in intestinal epithelial apoptosis compared with sham mice, which was further exacerbated in Vil-Cre/Ikkβf/δ 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/Ikkβf/δ 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/Ikkβf/δ 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/Ikkβf/ δ 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/Ikkβf/δ 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/Ikkβf/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.