Epidemiological and experimental data indicate chronic infection of the urinary tract is a significant risk factor for urinary bladder carcinogenesis. The mechanisms of the action, however, are not clear. In this study, we wish to focus on the role of the lipopolysaccharide (LPS) and LPS-associated protein(s), the cell wall components of pathogenic E. coli, in inducing urothelial hyperplasia and promoting carcinoma. We propose to test the hypotheses that urothelial hyperplasia is a regenerative (reparative) response to cytotoxicity of LPS or LPS-associated protein(s), that LPS is directly cytotoxic to urothelial cells allowing LPS to move from the bladder lumen to the submucosa. Chemotactic factors thus released by LPS-stimulated urothelial cells and by tumor necrosis factor secreted by LPS-stimulated macrophages will activate urothelial migration of neutrophils, which generate reactive oxygen intermediates and injure urothelial cells. Persistent urothelial hyperplasia induced in response to the injury promotes initiated cells to progress towards carcinoma.
The specific aims of this study are: 1. To examine whether repeated instillation of killed E. coli or LPS into the bladder lumen will induce progressive urothelial hyperplasia and ultimately carcinoma in N-methyl-N-nitrosoureainitiated urothelial cells; and 2. To investigate the possibility that neutrophils recruited into urothelium are responsible for urothelial injury and subsequent regenerative hyperplasia in a heterotopically transplanted rat urinary bladder (HTB) system and in cultured urothelial cells. These studies should clarify the role of chronic urinary tract infection in the development of urothelial carcinoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA033511-07A1
Application #
3171363
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1982-09-01
Project End
1993-12-30
Budget Start
1991-01-01
Budget End
1991-12-30
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
Schools of Dentistry
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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