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TNF is a key mediator in sepsis‐induced intestinal barrier dysfunction but is independent of enterocyte NFκB
Author(s) -
Samocha Alexandr J.,
Coopersmith Craig M.,
Dominguez Jessica A.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1004.2
Subject(s) - enterocyte , sepsis , tumor necrosis factor alpha , apoptosis , intestinal permeability , nf κb , evans blue , medicine , proinflammatory cytokine , inflammation , chemistry , endocrinology , small intestine , biochemistry
Inhibition of enterocyte NFκB augments sepsis‐induced intestinal hyperpermeability, gut apoptosis, and TNF expression. We hypothesized that TNF is a key mediator of gut barrier dysfunction and apoptosis in sepsis. Mice lacking enterocyte IKKβ (resultant NFκB inhibition) were created via Cre/lox recombination under control of the villin promoter. Wildtype (WT) and Vil ‐Cre/Ikkβ F/Ä (IKKβ −/− ) mice were injected 3 hr pre‐operatively with monoclonal anti‐TNF antibody or isotype control followed by cecal ligation and puncture (n=5–12/group). At 24 hr, intestinal permeability was assessed in vivo using FD4. Apoptosis was evaluated in crypts by active caspase‐3 staining. Blood was harvested for bacterial cultures. Anti‐TNF decreased permeability in septic WT (1832±321 vs. 4678±421 ng/ml; p<0.001) and septic IKKβ −/− mice (2528±446 vs. 6650±951 ng/ml; p<0.01). Sepsis‐induced apoptosis was decreased in both anti‐TNF treated septic WT (13±1 vs. 4±2; p<0.05) and septic IKKβ −/− mice (20±2 vs. 4±1; p<0.001). Anti‐TNF decreased bacteremia in septic WT (4×10 3 ±2×10 3 vs. 4×10 5 ±3×10 5 CFU/ml; p<0.05) and septic IKKβ −/− mice (500±500 vs. 3×10 6 ±2×10 6 CFU/ml; p<0.01). There were no differences between anti‐TNF treated groups for any parameter. TNF appears to be a key mediator in sepsis‐induced intestinal barrier dysfunction. However, this mechanism is independent of enterocyte NFκB. NIH GM66202 & GM082008.