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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK036869-03
Application #
3235414
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1987-01-01
Project End
1989-12-31
Budget Start
1989-01-01
Budget End
1989-12-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Los Angeles County Harbor-UCLA Medical Center
Department
Type
DUNS #
City
Torrance
State
CA
Country
United States
Zip Code
90509
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LeDuc, L E; Nast, C C (1990) Chemotactic peptide-induced acute colitis in rabbits. Gastroenterology 98:929-35
Cominelli, F; Nast, C C; Clark, B D et al. (1990) Interleukin 1 (IL-1) gene expression, synthesis, and effect of specific IL-1 receptor blockade in rabbit immune complex colitis. J Clin Invest 86:972-80
Cominelli, F; Nast, C C; Dinarello, C A et al. (1989) Regulation of eicosanoid production in rabbit colon by interleukin-1. Gastroenterology 97:1400-5
Leduc, L E; Zipser, R D (1989) Tissue origin of peptide-responsive eicosanoid production in rabbit intestine. Am J Physiol 257:G879-86
Cominelli, F; Dinarello, C A (1989) Interleukin-1 in the pathogenesis of and protection from inflammatory bowel disease. Biotherapy 1:369-75
Nast, C C; LeDuc, L E (1988) Chemotactic peptides. Mechanisms, functions, and possible role in inflammatory bowel disease. Dig Dis Sci 33:50S-57S
Zipser, R D (1988) Mediators of inflammation in inflammatory bowel disease. Dig Dis Sci 33:4S-5S
Schumert, R; Towner, J; Zipser, R D (1988) Role of eicosanoids in human and experimental colitis. Dig Dis Sci 33:58S-64S

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