Differences in cell proliferation and apoptosis between reversible and irreversible mucosal lesions associated with uracil-induced urolithiasis in N-butyl-N-(4-hydroxybutyl)nitrosamine-pretreated.

Differences between the reversible papillomatosis and preneoplastic lesions of the urinary bladder of rats were investigated in terms of cell proliferation and apoptosis after cessation of uracil administration. Animals were given N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks and then uracil for 8 weeks in order to induce urinary bladder lesions. During this period and after cessation of treatment until week 20, subgroups of animals were killed to allow sequential assessment of cell kinetics and apoptosis. Labeling indices (LI) in papillomatosis showed a marked elevation after 2 weeks of uracil treatment with a rapid decline thereafter. In contrast, LI in dysplasias, papillomas and carcinomas gradually elevated during the uracil treatment. Cessation of the uracil stimulation resulted in a complete disappearance of labeled cells in areas of papillomatosis accompanied by significant appearance of apoptotic bodies in the epithelial cells and shrinkage of the lesions. In the focal dysplasias and papillomas, however, any reduction in LI was temporary and followed by a rapid reelevation. The number of apoptotic bodies were relatively few in neoplastic lesions. Thus, removal of growth-stimulating uracil-calculi resulted in return of hyperplastic epithelium to normal by a homeostatically controlled apoptotic mechanism. In contrast, preneoplasias and neoplasias demonstrated an autonomous growth ability.