title: Tumor necrosis factor alpha increases intestinal permeability in mice with fulminant hepatic failure.
abstract: OBJECTIVE
  To determine the effect of tumor necrosis factor alpha (TNF-α) on intestinal permeability (IP) in mice with fulminant hepatic failure (FHF), and the expression of tight junction proteins.
  
  
  METHODS
  We selected D-lactate as an index of IP, induced FHF using D-galactosamine/lipopolysaccharide and D-galactosamine/TNF-α, assessed the results using an enzymatic-spectrophotometric method, transmission electron microscopy, immunohistochemistry, Western blotting and real-time quantitative polymerase chain reaction. The effect of the administration of anti-TNF-α immunoglobulin G (IgG) antibody, before the administration of D-galactosamine/lipopolysaccharide, on TNF-α was also assessed.
  
  
  RESULTS
  IP was significantly increased in the mouse model of FHF 6 h after injection (13.57 ± 1.70 mg/L, 13.02 ± 1.97 mg/L vs 3.76 ± 0.67 mg/L, P = 0.001). Electron microscopic analysis revealed tight junction (TJ) disruptions, epithelial cell swelling, and atrophy of intestinal villi. Expression of occludin and claudin-1 mRNA was significantly decreased in both FHF models (occludin: 0.57 ± 0.159 fold vs baseline, P = 0.000; claudin-1: 0.3067 ± 0.1291 fold vs baseline, P = 0.003), as were the distribution density of proteins in the intestinal mucosa and the levels of occludin and claudin-1 protein (occludin: 0.61 ± 0.0473 fold vs baseline, P = 0.000; claudin-1: 0.6633 ± 0.0328 fold vs baseline, P = 0.000). Prophylactic treatment with anti-TNF-α IgG antibody prevented changes in IP (4.50 ± 0.97 mg/L vs 3.76 ± 0.67 mg/L, P = 0.791), intestinal tissue ultrastructure, and the mRNA levels of occludin and claudin-1 expression (occludin: 0.8865 ± 0.0274 fold vs baseline, P = 0.505; claudin-1: 0.85 ± 0.1437 fold vs baseline, P = 0.1), and in the protein levels (occludin: 0.9467 ± 0.0285 fold vs baseline, P > 0.05; claudin-1: 0.9533 ± 0.0186 fold vs baseline, P = 0.148).
  
  
  CONCLUSIONS
  Increased in IP stemmed from the downregulation of the TJ proteins occludin and claudin-1, and destruction of the TJ in the colon, which were induced by TNF-α in FHF mice.
authors.affiliation: Department of Infectious Diseases, the First Affiliated Hospital, China Medical University, Shenyang 110001, Liaoning Province, China.
authors.forename: Guo-Zhen
authors.initials: GZ
authors.lastname: Li
authors.forename: Zhao-Han
authors.initials: ZH
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: Fu
authors.forename: Yu-Rong
authors.initials: YR
authors.lastname: Wang
authors.forename: Pei
authors.initials: P
authors.lastname: Liu
mesh_terms: D000818:Animals; D062445:Claudin-1 / Q000032:analysis / Q000235:genetics; D003106:Colon / Q000648:ultrastructure; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000648:ultrastructure; D019344:Lactic Acid / Q000032:analysis; D017114:Liver Failure, Acute / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D062793:Occludin / Q000032:analysis / Q000235:genetics; D010539:Permeability; D012333:RNA, Messenger / Q000032:analysis; D019108:Tight Junctions / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D062445:Claudin-1; C568113:Cldn1 protein, mouse; D062793:Occludin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019344:Lactic Acid