Thiruchelvam, Nikesh; (2003) The effects of experimental outflow obstruction on the developing bladder. Doctoral thesis (M.D), UCL (University College London).

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Abstract

In utero bladder outflow obstruction (BOO) of the human developing bladder, commonly caused by posterior urethral valves, produces significant bladder dysfunction with symptoms of urinary incontinence, poor bladder emptying and urinary tract infection. Furthermore, many of these boys suffer significant renal impairment. To investigate the antenatal events that lead to this postnatal dysfunction, I have used an experimental fetal ovine model of in utero BOO. I found that the obstructed fetal bladder became larger, heavier and had grown; this was accompanied by an increase in proliferation and apoptosis within the detrusor muscle layer and an increase of apoptosis with no increase in proliferation within the lamina propria layer. Also documented was a downregulation of the anti-death protein Bcl-2 and an upregulation of the pro-death protein Bax. Moreover, activated caspase-3, an effector of apoptotic death, was increased in obstructed bladders. I found the obstructed fetal bladder became hypocontractile and denervated and exhibited greater atropine-resistant contractions. Nitric oxide-mediated relaxations were also present. In addition, I observed increased compliance and reduced elasticity and viscoelasticity in the obstructed fetal bladder. My results suggest that enhanced apoptosis in detrusor smooth muscle cells appeared to be a part of a remodelling response during compensatory hyperplasia and hypertrophy. In the lamina propria, an imbalance between death and proliferation led to a relative depletion of cells. Furthermore, the obstructed fetal bladder became hypocontractile; in addition to denervation, this may result from a reduction in the elastic modulus that may prevent any extramuscular components from sustaining force. These discoveries provide insight into why the fetal bladder functions poorly postnatally when exposed to bladder outflow obstruction and suggests potential molecular avenues for fetal bladder manipulation. Future strategies will characterise the in vivo pressure changes after obstruction, contractile properties of isolated detrusor myocytes and changes in the 'deobstructed' obstructed fetal bladder.

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