Tumour necrosis factor-alpha affects blood-brain barrier permeability and tight junction-associated occludin in acute liver failure.
BACKGROUND
Cerebral oedema leading to cerebral herniation is a major cause of death during acute liver failure (ALF), but the underlying mechanism is not clear.


OBJECTIVE
We investigated the role of tumour necrosis factor (TNF)-alpha in changing the permeability of the blood-brain barrier (BBB) during ALF.


METHODS
ALF animal models were generated by administering D-galactosamine (GalN) and lipopolysaccharide, or GalN and TNF-alpha. ALF induction was blocked by first administering anti-TNF-alpha-IgG or anti-TNF-alpha-R1. We investigated the BBB permeability with Evans blue staining, and the structure with electron microscopy.


RESULTS
BBB permeability increased in ALF mice and correlated with elevated serum TNF-alpha levels. No vascular endothelial cell (EC) apoptosis was detected, but electron microscopy of cells from human and mouse ALF tissues revealed tight junction (TJ) disruptions and EC shrinkage, as well as increased vesicles and vacuoles. In addition, the expression of the TJ-associated protein occludin was significantly decreased in both ALF mice and patients, although the expression of occludin mRNA did not change. Changes in BBB permeability, brain tissue ultrastructure and occludin expression in ALF-induced mice could be prevented by prophylaxis treatment with either antibody to TNF-alpha-IgG or antibody to TNF-alpha-R1.


CONCLUSIONS
Our results suggest that TNF-alpha plays a critical role in the development of brain oedema in ALF, and that both vasogenic and cytotoxic mechanisms may be involved. Increased BBB permeability may be because of the disruption of TJs, and loss of the TJ-associated protein occludin.
Lv
Sa
S
Department of Infectious Diseases, the First Affiliated Hospital, China Medical University, Liaoning Province, China.
Song
Hong-Li
HL
Zhou
Ying
Y
Li
Li-Xin
LX
Cui
Wei
W
Wang
Wen
W
Liu
Pei
P
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001774:Blood Chemical Analysis; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects*; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005688:Galactosamine / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D017114:Liver Failure, Acute / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D062793:Occludin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019108:Tight Junctions / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*
D017931:DNA Primers; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine