The Effect Of PDTC On Bladder Fibrosis In Rats And The Possible Mechanism

Objective: To investigate the effect of NF-κB inhibitor pyrrole dithiocarbamate(PDTC)on bladder fibrosis in rats with partial bladder outlet obstruction(PBOO)and its possible mechanism.Methods: Seventy-five healthy adult SD rats with the body weight of 200±20g were selected and divided into 5 groups with 15 in each group according to random number table method:Normal control group(NORMAL)and sham operation control group,(SHAM),partial bladder outlet obstruction group(PBOO),pyrrolidine dithiocarbamate(PDTC)(50mg/kg/d)+ partial bladder outlet obstruction group(PDTC50mg/kg/d+PBOO),PDTC(100mg/kg/d)+ partial bladder outlet obstruction group(PDTC100mg/kg/d +PBOO).The sham group rats were opened the lower abdomen,and the bladder,urethra and surrounding tissues were separated without urethral ligation.PDTC group was intraperitoneally injected with PDTC(50mg/kg/d,100mg/kg/d)on the first day after surgery.The observation time of each group was 1 week,2 weeks and 4weeks.PBOO model was established by partial bladder neck ligation.All rats in each group received in vivo bladder pressure measurement under anesthesia to record bladder function,bladder weighing to evaluate the degree of fibrosis in bladder hypertrophy,which can reflect the process of bladder fibrosis caused by obstruction objectively.The expression of α-SMA,TGF-β1 and NF-κB p65 in bladder tissue was detected by immunohistochemistry,and the differences of expression among the groups were observed by statistical analysis.Results: 1.Compared with sham operation and control group,the bladder weight and the ratio of bladder weight to body weight were significantly increased by obstruction(P<0.05);HE staining showed significant proliferation of detrusor epithelial cells in those PBOO bladder.The bladder leak point pressure(BLPP)were highly increased by partial bladder outlet obstruction in rats under anethesia.2.There was no significant difference in the mean optical densities of α-SMA,TGF-β1and NF-κB p65 at 1W and 2W(P > 0.05),but there were significant differences at other different time periods(P <0.05).There was no significant difference between α-SMA group and normal control group(P > 0.05),while there were significant differences between α-SMA group and normal control group(P < 0.05).TGF-β1 control group and PDTC100mg/kg/d +PBOO had no statistical difference(P > 0.05),the other different experimental state comparison had statistical difference(P < 0.05).There was no significant difference in NF-κB p65 group between normal control group and sham operation group,between normal control group and PDTC100mg/kg/d +PBOO,and between sham operation group and PDTC100mg/kg/d +PBOO(P > 0.05).There were statistical differences in other experimental states(P < 0.05).Conclusion : 1.Incomplete bladder outlet obstruction can lead to bladder detrusor epithelium hyperplasia,increased bladder/body weight ratio,elevated bladder pressure,and induced uncontrolled proliferation,migration,and transformation of fibroblasts into myofibroblasts producing α-smooth muscle actin(α-SMA)and deposition of extracellular matrix components,which leading to bladder fibrosis in the end.2.PDTC,as an inhibitor of NF-κB,can effectively inhibit the entry of NF-κB into the nucleus of rat bladder.The mechanism may be related to the fact that PDTC inhibits the entry of NF-κB into the nucleus and reduces the expression of α-SMA,TGF-β1 and NF-κBp65.3.NF-κB inhibitor PDTC can alleviate the bladder hypertension level in the rat model of bladder outlet insufficiency obstruction,reduce the level of bladder structural remodeling,delay the progress of bladder fibrosis,and may become a new safe and effective clinical guidance drug.4.In the rat model of bladder outlet insufficiency obstruction,NF-κB signaling pathway may be one of the important signaling pathways of bladder fibrosis induced by pressure stimulation.