Hepatic encephalopathy: the role of inflammation, ammonia and
aquaporin expression in the pathogenesis of cerebral oedema.
Doctoral thesis, UCL (University College London).
Current evidence indicates synergy between hyperammonaemia and inflammation in the brain with liver failure. Utilising animal and laboratory experiments, this thesis explored a number of concise questions focused on progression to brain oedema and coma with hepatic encephalopathy (HE). STUDY 1: It is unclear whether the background cirrhotic state or hyperammonaemia predisposes to superimposed inflammation. Question 1: Does lipopolysaccharide (LPS)-induced systemic inflammation worsen brain oedema in cirrhotic bile duct-ligated rats? and is this associated with blood-brain barrier disruption? altered brain ammonia and/or inflammatory pathways? Answer 1: LPSinduced pre-coma/coma and exacerbated cytotoxic oedema, indicating synergy between hyperammonaemia and inflammation associated with brain protein nitrosation. STUDY 2: New ammonia-lowering therapies targeting multiple organs are necessary. Question 2: Does combining L-ornithine and phenylacetate (OP), synergistically improve ammonia reduction? Answer 2: L-ornithine and phenylbutyrate synergistically lead to sustained ammonia-lowering and limited oedema; L-ornithine detoxifying ammonia by providing a substrate for glutamine synthesis and phenylacetate renally excreting the glutamine as phenylacetylglutamine. STUDY 3: Despite apparent synergism, therapies for HE target either hyperammonemia or inflammation, not both. Question 3: Can a reduction in ammonia in cirrhotic rats prevent LPS-induced worsening of brain oedema and progression to pre-coma/coma? Does targeting hyperammonaemia and inflammation together provide therapeutic synergy? Answer 3: Ammonia primes the brain to the deleterious effect of LPS, with the ammonia-lowering effect of OP preventing LPS-induced coma and brain edema. STUDY 4: Aquaporin-4 (AQP4), a bi-directional astrocyte water channel, is thought to provoke brain oedema in neuropathic disorders. Question 4: Is AQP4 causally involved in the brain oedema associated with models of liver failure? Answer 4: AQP4 has no causal role in the brain edema associated with hyperammonemia or inflammation, with or without acute liver dysfunction. However in cirrhosis, AQP4 upregulation, with contemporaneous p38MAPK activation is possibly a compensatory response to inhibit edema formation.
|Title:||Hepatic encephalopathy: the role of inflammation, ammonia and aquaporin expression in the pathogenesis of cerebral oedema|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Institute of Hepatology|
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