(1) Department of Urology, Asan Medical Center, University of Ulsan, Seoul, South Korea, (2) Department of Urology, Pusan National University Yangsan Hospital, Yangsan, South Korea, (3) Department of Biomedical Sciences, Asan Medical Center, Seoul, Korea
The present study developed the interstitial cystitis (IC) rat model which represents important features of human IC bladder, such as impaired voiding function, denudated urothelium, increased inflammation, mast cell infiltration, and tissue fibrosis. Moreover, employing the IC rat model, we evaluated the therapeutic effect of NAC, a well-known anti-fibrotic agent.
To make IC rat model female 8-week-old Sprague-Dawley rats were given protamine sulfate (PS, 10mg) to bladder through PE-50 catheter in order to make denudation of urothelium. After 45 minutes the bladders were emptied, washed with buffer solution and then given a second treatment with lipopolysaccharide (LPS, 750ug) for 30 minutes in order to induce inflammation. Two times per week instillation of PS/LPS following this regimen over a period 5 weeks were used to induce a longer-lasting and possibly chronic injury to the urothelium. One week after final instillation of PS/LPS, 200mg/kg of NAC (n=10, IC + NAC) or PBS (n=10, IC) were daily intraperitoneal injection for 5 days. Ten rats were served as control. The therapeutic effect of NAC was examined by awake cystometry, histological and gene expression analysis after 1 week of NAC injection.
Functionally, LPS insult led to irregular micturition, decreased inter-contraction intervals, and decreased micturition volume. NAC significantly improved most of the voiding parameters and reversed histological damages including fibrosis. NAC inhibited the induction and nuclear localization of phospho-Smad2 protein in bladder tissues and the upregulation of genes related to fibrosis, such as Tgfb2, Tgfb3, Smad2, Smad3, Cxcl10, and Card10. This is the first study to demonstrate the beneficial effects on NAC in restoring voiding function, relieving tissue fibrosis and related bladder injuries in the LPS-induced cystitis rat model.
We demonstrated that NAC based therapy had beneficial effect to repair voiding function and regenerate denudated urothelium and relieve tissue fibrosis in the LPS-induced IC rat model. Through these findings, we propose NAC therapy as a new therapeutic approach to treat IC bladder.