The structural and molecular effects of elevated hydrostatic pressure and the role played by elevated hydrostatic pressure in the development of the functionally obstructed urinary bladder.

Bladder outflow obstruction is a common cause of morbidity and occasional mortality amongst the adult male population and less commonly in children. Clear evidence exists that elevated hydrostatic pressure within the urinary bladder of children is detrimental to the function of the upper renal tract, there is little known about the effects of elevated pressure on the structure and function of the bladder itself (McGuire et al. 1981). Heparin-binding epidermal growth factor-like growth factor is a potent mitogen, influencing many of the cell types found in the lower renal tract. There is evidence linking the effects of cellular stretch with changes in expression of this growth factor, however, little is known about the effects of elevated hydrostatic pressure on the expression of HB-EGF. We hypothesise that the expression of HB-EGF is influenced by elevated hydrostatic pressure and that HB-EGF is involved in the changes seen in the bladder with outflow obstruction. Our aims were to: 1) Reliably establish in vitro cultures of representative cell-lines from the bladder 2) Establish the mitogenic activities of HB-EGF in representative cell-lines from the bladder 3) Determine whether the expression of HB-EGF can be influenced by the application of elevated hydrostatic pressure and to see if there is a pressure threshold for such expression. 4) Establish a reliable animal model of elevated bladder outflow resistance and investigate the effects of elevated bladder outflow resistance on HB-EGF expression. Our results were as follows: We demonstrated that HB-EGF is a potent mitogen for bladder smooth muscle, interstitial and urothelial cells, inducing a hyperplastic response in all 3 cell-types and causing an increased surface area in smooth muscle and urothelial cells. HB-EGF expression was up-regulated in smooth muscle and interstitial cells in both a pressure and time-dependent manner. There was no change in the expression of the EGF receptor with elevated pressure. We were able to reliably characterise a novel animal model of elevated bladder outflow resistance and show a marked up-regulation of HB-EGF predominantly in the detrusor layer of the obstructed bladder. In summary, we demonstrate a role for HB-EGF as a mitogen in cells representative of the major components of the bladder wall. Such changes reflect those seen in the bladder with elevated outflow resistance and suggest a role for HB-EGF in the changes seen in the partially obstructed bladder.