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Lipopolysaccharide precipitates hepatic encephalopathy and increases blood-brain barrier permeability in mice with
Anne Chastre1, Mireille Bélanger, Bich N Nguyen
1Neuroscience Research Unit, Saint-Luc Hospital, CRCHUM, Montreal, QC, Canada.
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.
Methods:
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).
Results:
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.
Conclusions:
These findings represent the first direct evidence of inflammation-related BBB permeability changes in ALF.
Insights
Endotoxemia exacerbates acute liver failure (ALF) by increasing inflammation and altering blood-brain barrier (BBB) permeability, leading to hepatic encephalopathy (HE). This study provides direct evidence linking inflammation-induced BBB changes to HE progression in ALF.
Area of Science:
- Hepatology
- Neuroscience
- Immunology
Background:
- Acute liver failure (ALF) often involves infections, amplifying inflammation and potentially impacting the blood-brain barrier (BBB).
- Hepatic encephalopathy (HE) and increased mortality are common complications of ALF, often linked to central nervous system dysfunction.
- The role of endotoxemia in exacerbating HE and BBB permeability during ALF requires further investigation.
Purpose of the Study:
- To investigate the impact of endotoxemia on the progression of hepatic encephalopathy (HE) in acute liver failure (ALF).
- To determine the relationship between endotoxemia, BBB permeability, and HE progression in a mouse model of ALF.
Main Methods:
- Adult male mice with toxic liver injury-induced ALF were administered lipopolysaccharide (LPS) to model endotoxemia.
- Systemic inflammation, liver pathology, and BBB integrity were assessed.
- Progression of HE was monitored by the time to loss of corneal reflex (coma).
Main Results:
- LPS administration significantly increased circulating pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and worsened liver injury and hyperammonaemia.
- LPS treatment accelerated the onset of hepatic coma in ALF mice.
- The blood-brain barrier (BBB) became permeable to immunoglobulin G (IgG), with increased matrix metalloproteinase-9 (MMP-9) expression.
Conclusions:
- This study provides the first direct evidence that inflammation-induced changes in BBB permeability contribute to HE progression in ALF.
- Endotoxemia plays a critical role in exacerbating neurological complications in ALF by compromising BBB integrity.
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