Inhibition of IKKβ in enterocytes exacerbates sepsis-induced intestinal injury and worsens mortality.
OBJECTIVE
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.


METHODS
Prospective, randomized controlled study.


METHODS
Animal laboratories in university medical centers.


METHODS
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.


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.
1Department 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.
Jessica A
JA
Dominguez
Alexandr J
AJ
Samocha
Zhe
Z
Liang
Eileen M
EM
Burd
Alton B
AB
Farris
Craig M
CM
Coopersmith
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D020895:Enterocytes / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D023421:Models, Animal; D011446:Prospective Studies; D011897:Random Allocation; D018805:Sepsis / Q000378:metabolism* / Q000401:mortality*; D048069:Tumor Necrosis Factors / Q000494:pharmacology
D048069:Tumor Necrosis Factors; D051550:I-kappa B Kinase