by John M. Park, M.D.
One of the most challenging problems that we face as pediatric urologists is the management of children with obstructive uropathy. In particular, congenital obstruction of bladder outlet by posterior urethral valves creates many difficult problems related to incontinence, infection, and renal damage. The bladder's fundamental function - low pressure fluid storage and periodic emptying - is impaired when subjected to outlet obstruction. These clinical problems provide an impetus for my laboratory's focus.
We work primarily with animal models - surgically created bladder obstruction in rodents - to describe and examine the pattern of changes that mimic human situations. Once we identify a potential mechanism, we then attempt to test a specific mechanistic hypothesis using tissue culture and molecular biology techniques. These highly focused experiments yield new concepts and hypothesis, with which we test the physiological significance once again using animal models.
For example, we recently identified that cyclooxygenase-2 (COX-2), an important regulatory gene in prostaglandin synthesis was rapidly stimulated in bladder after obstruction (Park et al.,1997). This was a significant discovery because although it was known that prostaglandins were important in bladder pathophysiology, the mechanism by which prostaglandin synthesis occurred was largely unknown. We went on to identify that COX-2 expression occurred in the smooth muscle compartment and speculated that the principal stimulus may be an increase in mechanical stretch. We turned to tissue culture experiments wherein bladder smooth muscle cells were grown on silicone membranes and subjected to increased stretch using a computer-controlled, vacuum-driven strain inducing device (Park et al., 1999). We confirmed that mechanical stretch indeed stimulated COX-2 expression, and were able to quickly identify a novel agent with which we could suppress COX-2 gene activation. Now we are poised to return to our animal models to see whether we can modulate the pathological changes in bladder caused by obstruction. Our work was featured on the cover of the American Journal of Physiology (from January to June issues in 1999).
We believe that specific, hypothesis-driven investigations aimed at understanding the mechanism of bladder obstruction pathophysiology will enhance the management of other bladder diseases including painful bladder syndromes and benign prostatic hyperplasia and that it will promote the development of specific, etiology-based therapeutic strategies.
Park, J.M., Yang, T., Arend, L.J., M., S. A., Schnermann, J. B., and Briggs, J. B. (1997). Cyclooxygenase 2 is expressed in bladder during fetal development and stimulated by outlet obstruction. Am. J. Physiol. 273,F538-44.
Park, J. M., Yang, T., Arend, L. J., Schnermann, J. B., Peters, C. A., Freeman, M. R., and Briggs, J. P. (1999). Obstruction stimulates COX-2 expression in bladder smooth muscle cells via increased mechanical stretch. Am. J. Physiol. 276, F129-36.