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An Investigation of the Intestinal Epithelial Damage Response to Cytokines Produced During Inflammatory Bowel Disease and Sepsis.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	An Investigation of the Intestinal Epithelial Damage Response to Cytokines Produced During Inflammatory Bowel Disease and Sepsis./
作者:	Ikuomola, Felix Irewole.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	321 p.
附註:	Source: Dissertations Abstracts International, Volume: 83-06, Section: B.
Contained By:	Dissertations Abstracts International83-06B.
標題:	Inflammatory bowel disease. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28671101
ISBN:	9798538198337

An Investigation of the Intestinal Epithelial Damage Response to Cytokines Produced During Inflammatory Bowel Disease and Sepsis.
Ikuomola, Felix Irewole.

An Investigation of the Intestinal Epithelial Damage Response to Cytokines Produced During Inflammatory Bowel Disease and Sepsis. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 321 p.

Source: Dissertations Abstracts International, Volume: 83-06, Section: B.

Thesis (Ph.D.)--The University of Liverpool (United Kingdom), 2020.

This item must not be sold to any third party vendors.

Sepsis is a life-threatening host response to severe systemic infection that can result in multi-organ dysfunction syndrome (MODS) and organ failure. Globally, there are around 30 million cases of and 6 million deaths from sepsis annually. The intestine is one of the first organs to be damaged during the sepsis-induced proinflammatory cytokine production and hyperinflammatory responses. Similar processes occur in the intestinal mucosa during active inflammatory bowel disease (IBD). Under normal physiological conditions, the intestinal epithelium promotes gut homeostasis via mechanical protection and maintenance of structural integrity, and provides a physical barrier comprised of a continuous single cell layer of intestinal epithelial cells. Intestinal barrier dysfunction or compromised intestinal integrity potentially facilitates the passage of intestinal bacteria into the gut mucosa and blood circulation. Compromised intestinal barrier function occurs as a result of excessive epithelial cell shedding and apoptosis resulting from the direct effects of pro-inflammatory cytokines such as tumour necrosis factor (TNF) on intestinal epithelia. Understanding the mechanisms responsible for intestinal barrier function break down will potentially enable future prevention and treatment of sepsis, IBD and other conditions associated with intestinal barrier disruption. Recent advances in intestinal stem cell culture have enabled the generation of three-dimensional organoid cultures of the intestinal epithelium (termed enteroids) which can auto-propagate, auto-renew and contain similar cell populations to those found in the intestinal epithelium in vivo. This culture system represents a more physiological model of the intestinal epithelium than has previously been achievable using standard tissue culture techniques. It enabled investigation of tissue-level dynamics and the importance of NFκB signalling specifically in the intestinal epithelium in response to TNF (chapter 3). TNF treatment was associated with asynchronous expansions and contractions, increased motility, claudin-7 remodelling, reduced epithelial thickness and early increased surface area of enteroids. The alternative NFκB signalling pathway was demonstrated to regulate the intestinal epithelial response to injury and further exploration of other cytokines known to activate alternative pathway NFκB signalling was undertaken. We identified that other activators of NFκB signalling that are upregulated in the serum of patients with inflammatory conditions, such as TWEAK and LIGHT, were also capable of initiating the enteroid damage response and that Nfκb2-/- enteroids were resistant to these stimuli (chapter 4). Proteomic analyses were used to identify potential mechanisms responsible for altered intestinal epithelial dynamics in response to TNF including TNFaip3 and saa3. Proteomics elucidated the potential mechanistic drivers of the intestinal damage response during perturbed NFκB signalling (chapter 5). The enteroid inflammatory model was finally tested with corticosteroids, a non-steroidal anti-inflammatory drug and a natural anti-inflammatory compound found in the diet known to modulate NFκB signalling to determine whether this newly established in vitro model could be used to assess novel putative therapeutic interventions for sepsis and IBD (chapter 6). Further investigation is now warranted to determine the importance of TNF, other pro-inflammatory cytokines and alternative pathway NFκB signalling in regulating intestinal tissue level dynamics during health and disease and how these parameters may be modulated therapeutically to ameliorate the severity of IBD and sepsis.

ISBN: 9798538198337Subjects--Topical Terms:

3560376
Inflammatory bowel disease.

An Investigation of the Intestinal Epithelial Damage Response to Cytokines Produced During Inflammatory Bowel Disease and Sepsis.
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506 $a This item must not be sold to any third party vendors.
520 $a Sepsis is a life-threatening host response to severe systemic infection that can result in multi-organ dysfunction syndrome (MODS) and organ failure. Globally, there are around 30 million cases of and 6 million deaths from sepsis annually. The intestine is one of the first organs to be damaged during the sepsis-induced proinflammatory cytokine production and hyperinflammatory responses. Similar processes occur in the intestinal mucosa during active inflammatory bowel disease (IBD). Under normal physiological conditions, the intestinal epithelium promotes gut homeostasis via mechanical protection and maintenance of structural integrity, and provides a physical barrier comprised of a continuous single cell layer of intestinal epithelial cells. Intestinal barrier dysfunction or compromised intestinal integrity potentially facilitates the passage of intestinal bacteria into the gut mucosa and blood circulation. Compromised intestinal barrier function occurs as a result of excessive epithelial cell shedding and apoptosis resulting from the direct effects of pro-inflammatory cytokines such as tumour necrosis factor (TNF) on intestinal epithelia. Understanding the mechanisms responsible for intestinal barrier function break down will potentially enable future prevention and treatment of sepsis, IBD and other conditions associated with intestinal barrier disruption. Recent advances in intestinal stem cell culture have enabled the generation of three-dimensional organoid cultures of the intestinal epithelium (termed enteroids) which can auto-propagate, auto-renew and contain similar cell populations to those found in the intestinal epithelium in vivo. This culture system represents a more physiological model of the intestinal epithelium than has previously been achievable using standard tissue culture techniques. It enabled investigation of tissue-level dynamics and the importance of NFκB signalling specifically in the intestinal epithelium in response to TNF (chapter 3). TNF treatment was associated with asynchronous expansions and contractions, increased motility, claudin-7 remodelling, reduced epithelial thickness and early increased surface area of enteroids. The alternative NFκB signalling pathway was demonstrated to regulate the intestinal epithelial response to injury and further exploration of other cytokines known to activate alternative pathway NFκB signalling was undertaken. We identified that other activators of NFκB signalling that are upregulated in the serum of patients with inflammatory conditions, such as TWEAK and LIGHT, were also capable of initiating the enteroid damage response and that Nfκb2-/- enteroids were resistant to these stimuli (chapter 4). Proteomic analyses were used to identify potential mechanisms responsible for altered intestinal epithelial dynamics in response to TNF including TNFaip3 and saa3. Proteomics elucidated the potential mechanistic drivers of the intestinal damage response during perturbed NFκB signalling (chapter 5). The enteroid inflammatory model was finally tested with corticosteroids, a non-steroidal anti-inflammatory drug and a natural anti-inflammatory compound found in the diet known to modulate NFκB signalling to determine whether this newly established in vitro model could be used to assess novel putative therapeutic interventions for sepsis and IBD (chapter 6). Further investigation is now warranted to determine the importance of TNF, other pro-inflammatory cytokines and alternative pathway NFκB signalling in regulating intestinal tissue level dynamics during health and disease and how these parameters may be modulated therapeutically to ameliorate the severity of IBD and sepsis.
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