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Title: Exploring the mechanisms of organ dysfunction in acute-on-chronic liver failure
Author: Adebayo, Danielle
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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Short-term mortality of patients with acute-on-chronic liver failure (ACLF) is unacceptably high. As such, effective treatment for this syndrome is an unmet need. ACLF pathophysiology is complex and not completely understood. An improved understanding of the pathophysiological mechanisms involved in ACLF is key to developing effective treatment strategies. ACLF is characterised by an excessive systemic inflammatory response. Pathogen-associated molecular patterns (PAMPs) and Damage-associated molecular patterns (DAMPs) play an important role in mediating the excessive inflammatory response, cell death and subsequent organ failure in ACLF. The mechanism of cell death in this syndrome is poorly understood. Lipopolysaccharide (LPS) is a commonly implicated PAMP in ACLF that signals mainly via the Toll-like receptor 4 (TLR4) pathway. Following TLR4/LPS interaction, there is a release of pro-inflammatory cytokines and DAMPs such as extracellular adenosine triphosphate (ATP) which, signals via the P2X7 receptor pathway. It is known that the P2X7 receptor up-regulates interleukin (IL-1)-1 processing and release in LPS stimulated inflammatory cells. Furthermore, a crosstalk between LPS-dependent pathways and the P2X7 receptor has been suggested in the literature. The specific aims of this thesis were to address the following aims: (1) Investigate the mechanism of hepatic cell death in ACLF (2) Determine if recombinant alkaline phosphatase (recAP), an agent that detoxifies LPS and ATP, reduces severity of organ dysfunction in ACLF (3) Determine the effect of P2X7 receptor blockade on severity of renal dysfunction in an ACLF-AKI model. The predominant mode of hepatic cell death in ACLF is apoptosis. In addition, reducing LPS signalling via either the TLR4 or P2X7R pathway limits the severity of organ injury (liver, kidney and brain) in a rodent ACLF model. Thus, the development of agents that target these pathways, such as recAP, may provide a potential therapeutic tool for the management of ACLF.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available