This project seeks to isolate, purify, and characterize human mucosal mast cells from the colon, and to investigate how such cells are involved in the regulation of gastrointestinal physiology and pathophysiology. Human mucosal mast cells will be obtained from surgical specimens of human colon by enzymic dispersion, purified by centrigual elutriation, density gradients and/or negative selection techniques, and characterized according to the types and amounts of mediators they produce, and their responsiveness to degranulating and inhibitory agents. Attempts will also be made to grow; or maintain the cells in tissue culture either by establishing co-cultures between the mast cells and fibroblasts from various sources, or by using as potential sources of mast cell growth factors such agents as preparations from mitogen-stimulated human lymphocytes, or gibbon or murine IL-3. Having identified the types and amounts of mediators synthesized by mucosal mast cells, the ability of these mediators to cause colonic salt and water secretion will be tested using a model epithelium, the T84 cell line, and Using chamber methodology. The possibility that T84 cells can produce mediators capable of modulating mast cells function will also be investigated. Finally, mast cells will be obtained from intestinal tissue specimens of patients with inflammatory bowel disease, or other immune- related gastrointestinal diseases as available. The properties of such cells will be examined, and compared with those of normal mucosal mast cells in terms of mediator content, mechanisms of activation and inactivation, and control of growth and differentiation. In toto, the project should increase knowledge of the properties of human mast cells in health and disease. It is hoped that definitive information will be derived as to whether mucosa mast cells play a role in he regulation of intestinal physiology, such as the control of electrolyte transport, and/or the generation of intestinal pathology, such as in inflammatory bowel disease. A role for mast cell activation has been postulated in the generation of inflammatory bowel disease, and other immune-related gastrointestinal disorders, but has not been conclusively demonstrated. Inflammatory bowel disease represents a significant, and increasing, cause of morbidity and mortality, especially in developed countries. This study may shed more light n these conditions, and thus suggest new therapeutic modalities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI024992-03
Application #
3454212
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1988-07-01
Project End
1993-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Pratha, V S; Thompson, S M; Hogan, D L et al. (1998) Utility of endoscopic biopsy samples to quantitate human duodenal ion transport. J Lab Clin Med 132:512-8
Myers, C P; Hogan, D; Yao, B et al. (1998) Inhibition of rabbit duodenal bicarbonate secretion by ulcerogenic agents: histamine-dependent and -independent effects. Gastroenterology 114:527-35
Gelbmann, C M; Barrett, K E (1995) Role of histamine in a rat model of colitis. Inflamm Res 44:386-92
Gelbmann, C M; Schteingart, C D; Thompson, S M et al. (1995) Mast cells and histamine contribute to bile acid-stimulated secretion in the mouse colon. J Clin Invest 95:2831-9
Hogan, D L; Yao, B; Barrett, K E et al. (1995) Histamine inhibits prostaglandin E2-stimulated rabbit duodenal bicarbonate secretion via H2 receptors and enteric nerves. Gastroenterology 108:1676-82
Barrett, K E (1995) Effect of the diglyceride lipase inhibitor, RG80267, on epithelial chloride secretion induced by various agents. Cell Signal 7:225-33
Chin, K W; Barrett, K E (1994) Mast cells are not essential to inflammation in murine model of colitis. Dig Dis Sci 39:513-25
Yen, A; Mathieu-Costello, O; Gigli, I et al. (1994) Inhibition of mast cell mediator secretion induced by protoporphyrin plus long-wave ultraviolet light: a morphometric and ultrastructural analysis. J Allergy Clin Immunol 93:909-18
Barrett, K E; Bigby, T D (1993) Involvement of arachidonic acid in the chloride secretory response of intestinal epithelial cells. Am J Physiol 264:C446-52
Vajanaphanich, M; Kachintorn, U; Barrett, K E et al. (1993) Phosphatidic acid modulates Cl- secretion in T84 cells: varying effects depending on mode of stimulation. Am J Physiol 264:C1210-8

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