Anthony, Daniel Cabel Clive; (1994) The development and use of a new animal model for inflammatory bowel disease. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Inflammatory bowel disease (IBD) is of unknown aetiology. A clinically relevant animal model of IBD is essential for our understanding of intestinal inflammation and for evaluating drug efficacy and mode of action. A new animal model for IBD was induced in rabbits by a single intracolonic instillation of trinitrobenzene sulphonic acid (TNB) in a 25 per cent ethanol solution. This produced a dose-dependent inflammation and ulceration that persisted for up to six weeks. A detailed histopathological study showed that the model had many features of IBD. Inappropriate activity of the matrix metalloproteinase enzymes is implicated in tissue destruction; in IBD there is consistent expression of the matrix metalloproteinases, which are not present in normal colon. The temporal and spatial distribution of the matrix metalloproteinases - collagenase, stromelysin, and gelatinase - and their inhibitor, tissue inhibitor of metalloproteinase, were investigated in the model by means of immunolocalisation. The findings suggest that it is the differential expression of these enzymes that is significant in ulcer formation and fibrosis in IBD. The effect of methylprednisolone on the pathogenesis of the model was examined using; immunoassay of arachidonic acid metabolites, computer-aided image analysis of the macroscopic appearance, and histological assessment. Methylprednisolone did not modify the macroscopic damage or influence arachidonic acid metabolism, but did reduce neutrophil infiltration. These results suggest that neutrophils are not responsible for the damage observed in this model. Experiments to investigate the response of the model to a second challenge with TNB suggest that a type IV hypersensitivity reaction is not the underlying immunological mechanism. The new model should prove a valuable tool for further studies in the pathophysiology and treatment of inflammatory bowel disease.

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