Tumour necrosis factor-α affects blood-brain barrier permeability and tight junction-associated occludin in acute liver failure

Abstract

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. Aims: We investigated the role of tumour necrosis factor (TNF)-a 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-α. ALF induction was blocked by first administering anti-TNF-α-IgG or anti-TNF-α-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-α 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-α-IgG or antibody to TNF-α-R1. Conclusions: Our results suggest that TNF-α 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. © 2010 John Wiley & Sons A/S.