The etiology of ulcerative colitis is unknown; however, there is increasing evidence that the inflammation is mediated in part by eicosanoids (prostaglandins, thromboxanes and leukotrienes). Eicosanoid production is markedly enhanced in experimental colitis and in human colitis. Our long-term aims are to determine the origin, regulation and function of these eicosanoids, which may lead to new therapeutic strategies. This application is limited to rabbit models of acute colon inflammation. Two immune models, cell-mediated (dinitrochlorobenzene hypersensitivity) and immune-complex deposition injury, are used to determine 1) the cells that produce eicosanoids (with in vitro incubations, isolated cell preparations, and enzyme immunofluorescence), 2) the hormonal and inflammatory stimuli that affect eicosanoid production (with ex vivo perfusions), 3) the relationship of eicosanoids to inflammation (with in vivo rectal dialysis, specific histologic criteria, and eicosanoid inhibitors) and 4) the role of eicosanoids in altered colon blood flow (with microsphere and laser-doppler methods and eicosanoid inhibitors). Our original model uses rectal instillation of the chemotactic peptide F-met-leu-phe that may directly induce inflammation by stimulation of leukotrienes from healthy colon. This new model is used to assess the relationship of in vivo leukotriene production (by rectal dialysis) to inflammation and to assess the effects of lipoxygenase inhibitors on inflammation. The F-met-leu-phe studies also demonstrate that cells in healthy colons can produce large amounts of leukotrienes, and these cells will be indentified by incubation of isolated cell preparations with agonists. PGE2, PGI2, TxB2, LTB4 and LTC4 are measured by radioimmunoassay and validated with radiochromatography, HPLC with UV absorbance, bioassay and/or mass spectrometry. Emphasis in all studies is on extensive validation of assays, collection techniques, and use of inhibitors by comparison of several methods or several drugs.
Showing the most recent 10 out of 11 publications
