Ray, Shuvra;
(2020)
The role of the renin angiotensin system and its principal receptor AT1 in the pathogenesis of intestinal fibrosis in inflammatory bowel disease.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Fibrosis is the common pathological end point of many diverse medical conditions and greatly contributes to mortality and morbidity. It can affect any major organ in the human body; it is usually a sequela of chronic inflammation and related to aberrant wound healing processes. Despite major advances in the treatment of recurrent severe gut inflammation characteristic of inflammatory bowel disease (IBD) there has been no tangible progress in reversing gut fibrosis and its complications such as intestinal strictures necessitating surgical resection. This is partly due to our limited understanding of the mechanisms and key molecular participants underlying fibrogenesis. Fibrosis in the gut is difficult to study and thus many advances in this field are initially discovered in other organs. There is now a substantial body of evidence showing that the renin-angiotensin system and its principal receptor AT1 play a central role in fibrosis in multiple organ systems. Furthermore, the oral AT1 receptor antagonist losartan has been shown in multiple studies to reduce fibrogenesis in vitro, in animal studies and in pilot clinical studies. This thesis makes an original contribution to our knowledge by first exploring the hypothesis that the AT1 receptor is upregulated in human IBD and gut fibrosis. Secondly, it examines the effects of AT1 stimulation and blockade with losartan in vitro on pro-fibrogenic cells. Thirdly, this research describes and validates a novel high fidelity mouse model of small bowel fibrosis. Finally I conclude by using this model to examine the in vivo effects of losartan on fibrosis at different stages of disease before assessing the effects of losartan on fibrosis following suppression of inflammation with steroids. These data provide the necessary evidence to justify a clinical trial of losartan in IBD.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The role of the renin angiotensin system and its principal receptor AT1 in the pathogenesis of intestinal fibrosis in inflammatory bowel disease |
| Event: | UCL |
| 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 > 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 UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10103019 |
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