Cholecystitis and colitis are inflammatory disorders which occur spontaneously and in response to a variety of stimuli. It is important to improve our understanding of why these epithelial inflammatory processes occur and to attempt to identify mechanisms to prevent and treat the disorders. Previous studies have demonstrated that cyclooxygenase inhibitors are specific drugs for the treatment of gallbladder disease. Gallbladder and colonic epithelial cells respond to inflammatory agents with specific alterations in production of prostanoids and platelet- activating factor, indicating that these cells have significant phospholipase A2 and cyclooxygenase activity. Stimulated by inflammatory agents, gallbladder epithelial cells produce 14 kDa phospholipase A2 and 72 kDa cyclooxygenase-2. ln-vivo exposure of animal gallbladders to various inflammatory stimuli results in mucosal cell necrosis. In-vitro, the inflammatory stimuli produce production of inflammatory mediators, however, these inflammatory stimuli and mediators in tissue culture media have no effect on cell integrity. The proposed research will be directed at evaluating the involvement of and interaction of epithelial cells, adhesion molecules, and leukocytes in mucosal cell necrosis. The relationships of mucosal cell inflammatory processes to eicosanoid formation is complex. Evaluation of the formation and control of the rate limiting enzymes cyclooxygenase- l, and cyclooxygenase-2 in these cell systems will increase our understanding of the role of the eicosanoids in cholecystitis and colitis. The production of the inflammatory mediator, platelet-activating factor by mucosal cells from the gallbladder and colon indicates that the cells have significant phospholipase A2 activity. Understanding of the mechanisms of epithelial cell inflammatory disorders will require improved understanding of the induction and expression of the secretory type II 14-kDa phospholipase A2 and 85-kDa arachidonyl selective type IV phospholipase A2. Protein production by mucosal cells occurs in response to inflammatory stimuli. We intend to evaluate the factors controlling protein production and to characterize the specific proteins produced. Epithelial inflammatory disorders may predispose the gallbladder mucosal cells and colonocytes to malignant transformation. We will evaluate the role of cyclooxygenase-2 in epithelial cell mitogenesis. The above described research will contribute to improved understanding of the mechanisms of the development of cholecystitis and colitis and provide information to assist in the development of preventative and therapeutic agents for these important clinical disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK027695-14
Application #
2900148
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Serrano, Jose
Project Start
1981-01-01
Project End
2000-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
14
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
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Grossman, E M; Longo, W E; Panesar, N et al. (2000) The role of cyclooxygenase enzymes in the growth of human gall bladder cancer cells. Carcinogenesis 21:1403-9
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Longo, W E; Grossmann, E M; Erickson, B et al. (1999) The effect of phospholipase A2 inhibitors on proliferation and apoptosis of murine intestinal cells. J Surg Res 84:51-6
Erickson, B A; Longo, W E; Panesar, N et al. (1999) The effect of selective cyclooxygenase inhibitors on intestinal epithelial cell mitogenesis. J Surg Res 81:101-7
Longo, W E; Panesar, N; Mazuski, J et al. (1998) Contribution of cyclooxygenase-1 and cyclooxygenase-2 to prostanoid formation by human enterocytes stimulated by calcium ionophore and inflammatory agents. Prostaglandins Other Lipid Mediat 56:325-39
Longo, W E; Erickson, B; Panesar, N et al. (1998) The role of selective cyclooxygenase isoforms in human intestinal smooth muscle cell stimulated prostanoid formation and proliferation. Mediators Inflamm 7:373-80
Longo, W E; Damore, L J; Mazuski, J E et al. (1998) The role of cyclooxygenase-1 and cyclooxygenase-2 in lipopolysaccharide and interleukin-1 stimulated enterocyte prostanoid formation. Mediators Inflamm 7:85-91
Solomon, H; Contis, J; Li, A P et al. (1996) The effect of prostanoids on hepatic bile flow in dogs with normal liver and bile duct cell hyperplasia. Prostaglandins Leukot Essent Fatty Acids 54:265-71
Kaminski, D L; Roque, M A; Li, A P (1996) Role of protein kinase A in human hepatocyte DNA synthesis. Dig Dis Sci 41:1014-21

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