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Investigation of the acute inflammatory response in Crohn's disease.

Marks, D.J.B.; (2006) Investigation of the acute inflammatory response in Crohn's disease. Doctoral thesis , University of London. Green open access

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Abstract

Most theories concerning the primary cause of Crohn's disease focus on over-activation of the immune response. Paradoxically, the defect may instead relate to diminished acute inflammation. Neutrophil accumulation to sites of dermal trauma has been shown to be reduced. Were the same phenomenon to occur in the gut, it might impair bacterial clearance thus provoking granuloma formation. In this thesis, a novel technique demonstrated attenuated neutrophil accumulation following trauma to the bowel. A modified skin window technique linked this failure of migration to defective IL-8 production. Polymorphisms in CARD15, associated with susceptibility to Crohn's disease, compounded the problem by abrogating the normal pro-inflammatory action of the protein but did not underlie the basic phenotype. Consequently, the response of macrophages to other inflammatory agonists was examined. IL-8 production was also impaired in Crohn's disease after stimulation with wound fluid, C5a or TNF-a. The response of Crohn's patients to gut bacteria was assessed directly in vivo by subcutaneous injection of killed Escherichia coli. This elicited substantial local inflammation in controls, manifested by an NO-mediated increase in blood flow. The response was considerably lower in Crohn's patients, particular those with colonic disease. In contrast, acute phase reactants were highest in the latter, supporting the hypothesis that an impaired local response can drive a systemic pro inflammatory state. The demonstration of attenuated acute inflammation in Crohn's disease may have important implications for understanding its pathogenesis and targeting novel therapies.

Type: Thesis (Doctoral)
Title: Investigation of the acute inflammatory response in Crohn's disease.
Identifier: PQ ETD:592172
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Nephrology
URI: https://discovery.ucl.ac.uk/id/eprint/1444862
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