A portion of the results described in this manuscript was presented at the annual meeting of the AASLD, Boston, October 2012, and published in abstract form Hepatology, 956A, 2012.
Cirrhosis and Liver Failure
Lipopolysaccharide precipitates hepatic encephalopathy and increases blood–brain barrier permeability in mice with acute liver failure
Article first published online: 2 AUG 2013
© 2013 John Wiley & Sons A/S. Publishing by John Wiley & Sons Ltd.
Volume 34, Issue 3, pages 353–361, March 2014
How to Cite
Liver Int. 2014: 34: 353–361
- Issue published online: 7 FEB 2014
- Article first published online: 2 AUG 2013
- Accepted manuscript online: 19 JUN 2013 12:40AM EST
- Manuscript Accepted: 31 MAY 2013
- Manuscript Revised: 16 MAY 2013
- Manuscript Received: 3 APR 2013
- The Canadian Institutes of Health Research
- acute liver failure;
- blood–brain barrier;
- immunoglobulin G extravasation;
- matrix metalloproteinase-9;
- pro-inflammatory cytokines;
- systemic inflammatory response
Background & Aims
Acute liver failure (ALF) is frequently complicated by infection leading to precipitation of central nervous system complications such as hepatic encephalopathy (HE) and increased mortality. There is evidence to suggest that when infection occurs in ALF patients, the resulting pro-inflammatory mechanisms may be amplified that could, in turn, have a major impact on blood–brain barrier (BBB) function. The aim of this study was to investigate the role of endotoxemia on the progression of encephalopathy in relation to BBB permeability during ALF.
Adult male C57-BL6 mice with ALF resulting from azoxymethane-induced toxic liver injury were administered trace amounts of the endotoxin component lipopolysaccharide (LPS). Effects on the magnitude of the systemic inflammatory response, liver pathology and BBB integrity were measured as a function of progression of HE, defined as time to loss of corneal reflex (coma).
Lipopolysaccharide caused additional two- to seven-fold (P < 0.001) increases in circulating pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), worsening liver pathology and associated increases of circulating transaminases as well as increased hyperammonaemia consistent with a further loss of viable hepatocytes. LPS treatment of ALF mice led to a rapid precipitation of hepatic coma and the BBB became permeable to the 25-kDa protein immunoglobulin G (IgG). This extravasation of IgG was accompanied by ignificant up-regulation of matrix metalloproteinase-9 (MMP-9), an endopeptidase known to modulate opening of the BBB in a wide range of neurological disorders.
These findings represent the first direct evidence of inflammation-related BBB permeability changes in ALF.