Radiation-induced changes in transforming growth factor beta and collagen expression in the murine bladder wall and its correlation with bladder function.

Late radiation-induced changes in transforming growth factor beta (TGF-beta), collagen I and collagen III content of the bladder wall, as well as morphological alterations of the uroepithelium, were analyzed quantitatively in an immunohistochemical study. An interlaboratory, i.e. interstrain, comparison of two mouse strains (Amsterdam C3H/Hen Af-nu+ and Munich C3H Neu) with different dose-effect relationships for late bladder damage was made, choosing radiation doses producing equivalent functional alterations in both strains (ED80 of 25 Gy and 19 Gy, respectively, 40 weeks after irradiation). In one strain of mouse, cystometry was also performed in the same animals at different times after irradiation. The TGF-beta staining intensity showed a progressive increase between 90 and 360 days after irradiation. This increase was similar in both strains of mouse treated with functionally equivalent doses (ED80) and was less pronounced after a lower, ED40, dose in the Munich mice. In both strains, there was a radiation-induced increase in both collagen subtypes from 180 days after irradiation with the ED80. The ratio of collagen type I/III, however, decreased in the Amsterdam mice and increased in the Munich mice. The relative radioresistance of the Amsterdam mice may therefore be partly due to a greater contribution of the elastic collagen type III, affording greater bladder compliance after irradiation. The extent of radiation-induced uroepithelial denudations or papillomatous outgrowths, the TGF-beta staining intensity and collagen I/III ratio were each correlated to bladder function determined by cystometry for the Munich mice. This correlation was statistically significant for all three parameters for group mean responses and, with the exception of the collagen I/III ratio, also for individual mice. These experiments indicate that chronic radiation-induced alterations in TGF-beta expression and connective tissue metabolism in the bladder wall are possibly important factors determining reduced bladder function after irradiation.