Obstruction stimulates COX-2 expression in bladder smooth muscle cells viaincreased mechanical stretch

Studies were performed to investigate the regulatory mechanism of bladder c yclooxygenase-2 (COX-2) expression after outlet obstruction. In situ hybrid ization of murine bladder tissues using COX-2-specific riboprobes demonstra ted that COX-2 expression was induced predominantly in the bladder smooth m uscle cells after outlet obstruction. To study the effect of increased mech anical stretch on COX isoform expression, cultured rat bladder smooth muscl e cells were grown on silicone elastomer-bottomed plates coated with collag en type I and were subjected to continuous cycles of stretch/relaxation for variable duration. COX-1 mRNA levels did not change with stretch. COX-2 ex pression increased in a time-dependent manner after stretch, with maximal m RNA and protein levels occurring after 4 h. PGE(2) levels increased more th an 40-fold in the culture media after stretch, consistent with increased CO X activity, and this was reduced to near completion in the presence of a CO X-2 inhibitor, NS-398. Exposure to stretch over a 48-h period induced a 4.7 +/- 0.6-fold increase in tritiated thymidine incorporation rate. This incr ease in DNA synthesis was markedly suppressed when the cells were stretched in the presence of NS-398. We conclude that in bladder obstruction COX-2 a ctivation occurs predominantly in the smooth muscle cells in response to me chanical stretch. Our findings also suggest that stretch-activated COX-2 ex pression may participate in bladder smooth muscle cell proliferation and th ereby play a role in pathological bladder wall thickening after obstruction .