Tumor necrosis factor-α affects blood-brain barrier permeability in acetaminophen-induced acute liver failure

Objectives Cerebral edema is a major cause of death during acute liver failure (ALF), but the exact mechanism of this condition is still not entirely clear. The aim of this study was to investigate the role of tumor necrosis factor alpha (TNF alpha) in changing the permeability of the blood-brain barrier (BBB) during acetaminophen (APAP)-induced ALF. Materials and methods ALF animal models were generated by administering APAP. Anti-TNF alpha-IgG was intravenously injected (100 mu g/mouse) 2 h after administration of APAP. We investigated BBB permeability with Evans blue staining, and structure with electron microscopy. Results BBB permeability increased in APAP-induced ALF mice and correlated with elevated serum TNF alpha levels. Electron microscopy of mouse brain tissues revealed tight junction (TJ) disruptions and endothelial cell shrinkage, as well as increased vesicles and vacuoles. In addition, the expression of the TJ-associated protein, occludin, was significantly decreased in APAP-induced ALF mice. Changes in BBB permeability and occludin expression could be prevented by administering anti-TNF alpha-IgG 2 h after APAP challenge. Conclusion TNF alpha plays a critical role in the development of brain edema in APAP-induced ALF. Increased BBB permeability may be due to the loss of the TJ-associated protein occludin. Eur J Gastroenterol Hepatol 23:552-558 (c) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.