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Modulation of inflammation in the reduction of intra hepatic resistance

Sharma, V; (2018) Modulation of inflammation in the reduction of intra hepatic resistance. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

In cirrhosis, there is a dichotomy in the haemodynamic abnormality in the intra hepatic and splanchnic circulation, as a result of an imbalance between vasoactive agents. In the intra-hepatic circulation, there is vasoconstriction secondary to endothelial dysfunction and vasodilatation in the splanchnic circulation which is provoked by a multitude of mechanisms. Inflammation has been also implicated in propagation of the haemodynamic abnormalities of portal hypertension in patients with acute on chronic liver failure (ACLF). The studies conducted in this thesis aim to understand how modulating inflammation leads to the reduction of intra hepatic resistance. In the first part of the thesis, I validated the bile duct ligated rat model for my studies. I establish ADRA2a adrenergic receptor as the target receptor in this model to treat portal hypertension. I was able to show that a specific ADRA2a adrenergic receptor antagonist was able to improve the haemodynamic and inflammatory parameters. This strategy was also able to improve the function of the immune cells in this model. This provided a proof-of-concept for ADRA 2a adrenergic receptor as a target for intervention in ACLF to reduce inflammation and thereby reduce portal pressure. In the second section of the thesis, I studied the role of arginine in the modulation of portal hypertension in a bile duct ligated rat model of cirrhosis. Thereafter, I showed a significant lowering of portal pressure in a BDL model of cirrhosis by L-Arginine supplementation via modulation of the NO-ADMA-DDAH and inflammatory pathway. The findings from this study provides the basis for novel agents for the treatment of portal hypertension. .The studies conducted within the remit of this thesis provides valuable insight into the pathophysiology of portal hypertension and alludes to an alternative management strategy for portal hypertension.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Modulation of inflammation in the reduction of intra hepatic resistance
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2018. 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. Third party copyright material has been removed from ethesis.
UCL classification: 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 Population Health Sciences > Institute of Cardiovascular Science
URI: https://discovery.ucl.ac.uk/id/eprint/10060376
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