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<https://discovery.ucl.ac.uk/id/eprint/10192493> <http://purl.org/dc/terms/title> "The role of hepatic cell death in the acute\r\ndecompensation of cirrhotic liver disease"^^<http://www.w3.org/2001/XMLSchema#string> .
<https://discovery.ucl.ac.uk/id/eprint/10192493> <http://purl.org/ontology/bibo/abstract> "Whilst the acute decompensation of cirrhosis (AD) is a common presentation to\r\nhospital it is associated with significant mortality through the evolution of multi-organ\r\nfailure a syndrome termed acute-on chronic liver failure (ACLF) for which there is little\r\nwidely available treatment. Whilst the pathobiology of this process is not well\r\nunderstood it is clear that systemic inflammation plays an important role. Small studies\r\nhave also demonstrated that hepatic cell death is associated with AD and ACLF but\r\nthis was not well described and its role is unclear. The main aims of this thesis were\r\nto i) describe the pattern of cell death markers in AD and ACLF in comparison to health\r\nand stable cirrhosis ii) explore the contribution of the regulated form of necrosis termed\r\nnecroptosis to AD and ACLF and iii) explore the role of histones derived from hepatic\r\ncell death as triggers for the aggravation of portal hypertension seen in AD and ACLF.\r\nInitial experiments confirmed marked elevation of markers of hepatic cell death in\r\npatients with AD and ACLF as opposed to stable cirrhosis or health and that levels\r\nrose in line with clinical severity moving from primarily apoptotic cell death towards\r\nmore immunogenic non-apoptotic modes of cell death.\r\nFurther experiments demonstrated elevated plasma and histological markers of\r\nnecroptosis in human ACLF and these findings were recapitulated in the BDL+LPS\r\nrodent model of ACLF. Additionally, RIPK1 blockade, a key necroptosis kinase, was\r\nfound to reduce liver injury and modulate multi-organ injury.\r\nFinally, experiments demonstrated that cell death derived histone is a potent activator\r\nof TLR4 receptors, able to drive human hepatic stellate cell contraction and activation\r\nand that human albumin solution (HAS) is able to mitigate these affects. Furthermore,\r\nHAS administration in a rodent model of AD and ACLF significantly reduced both portal\r\npressure and circulating histone levels.\r\nIn summary hepatic cell death is a key feature of AD and ACLF and severity of cell\r\ndeath reflects the severity of the clinical presentation. Necroptosis is of pathobiological\r\nrelevance in ACLF and histone production from hepatic cell death is able to directly\r\naggravate portal hypertension by hepatic stellate cell activation and this can be\r\nmodulated by albumin administration."^^<http://www.w3.org/2001/XMLSchema#string> .
<https://discovery.ucl.ac.uk/id/eprint/10192493> <http://purl.org/dc/terms/date> "2024-06-28" .
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