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Exploring the mechanisms of organ dysfunction in acute-on-chronic liver failure

Adebayo, Danielle; (2020) Exploring the mechanisms of organ dysfunction in acute-on-chronic liver failure. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

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.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Exploring the mechanisms of organ dysfunction in acute-on-chronic liver failure
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10089762
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