Prevention of urethral fibrosis induced by transforming growth factor beta 1 using selective Wnt/ß-catenin signaling inhibitors in a rat model.

OBJECTIVES: To determine the anti-fibrotic effects of Wnt/ß-catenin signaling inhibitors on urethral stricture. METHODS: Human fibroblasts were exposed to transforming growth factor beta 1 combined with various concentrations of Wnt/ß-catenin inhibitors (ICG-001, IWR-1, and PRI-724), and cell proliferation and migration were evaluated. Urethral fibrosis was induced in male Sprague-Dawley rats by urethral injection of transforming growth factor beta 1 and co-treatement with inhibitors. Urethral tissues were harvested 2 weeks after the injection. The messenger ribonucleic acid and protein expression was examined for fibrosis markers Axin-1, collagen type 1, alpha smooth muscle actin, and ß-catenin. Histological analysis of fibrosis and collagen deposition was also performed. RESULTS: Cell migration was ameliorated by ICG-001 and PRI-724. Protein and messenger ribonucleic acid expression of collagen type 1 and alpha smooth muscle actin in transforming growth factor beta 1-treated fibroblasts decreased in a concentration-dependent manner with the ICG-001 and PRI-724 treatments (P < 0.05). However, there were no significant changes with the IWR-1 treatment. Collagen type I and alpha smooth muscle actin messenger ribonucleic acid and protein expression were both significantly increased in the urethral tissues of rats with transforming growth factor beta 1-induced urethral fibrosis. Rats co-treated with ICG-001 or PRI-724 showed relatively mild fibrosis and significantly reduced collagen type I and alpha smooth muscle actin messenger ribonucleic acid and protein expression (P < 0.05). CONCLUSIONS: ICG-001 and PRI-724 significantly ameliorated urethral fibrosis induced by transforming growth factor beta 1 in rats. These results suggest that ICG-001 and PRI-724 can be developed as therapeutics for treating urethral stricture.

An Experimental Model of Anterior Urethral Stricture in Rabbits With Local Injections of Bleomycin.

OBJECTIVE: To develop an experimental model of anterior urethral stricture in rabbits using a bleomycin (BLM) injection technique. MATERIALS AND METHODS: Thirty adult male New Zealand rabbits were randomly divided into 4 groups. In group 1 (BLM group), BLM was injected into the urethral submucosal tissue every other day through a catheter for 6 weeks at the 3-, 6-, 9-, and 12-o'clock positions of the urethra in 12 rabbits. In group 2 (phosphate-buffered saline [PBS] group), PBS was injected instead of BLM in 6 rabbits. In group 3 (stricture control group), an 8 × 20 mm urethral defect was created in 6 rabbits. In group 4 (normal group), 6 normal rabbits were included. All rabbits in the PBS group and stricture control group, as well as 6 rabbits in the BLM group, were sacrificed at 6 weeks. The remaining 6 rabbits in the BLM group were sacrificed at 10 weeks. Urethrography was performed in all rabbits before sacrifice, and the urethra was harvested for histologic analysis. RESULTS: All rabbits in the BLM group showed mild urethral stricture at 4 weeks and significant urethral stricture at 6 weeks, without spontaneous resolution of the stricture at 10 weeks. No urethral stricture was observed in the PBS group at 4 and 6 weeks. Histologic examination confirmed the presence of fibrosis in the BLM group without spontaneous improvement. CONCLUSION: BLM injection can induce an experimental model of anterior urethral stricture in rabbits. This simple, highly efficient, reproducible method can be carried out in any laboratory.

Transforming Growth Factor-ß1 Induced Urethral Fibrosis in a Rat Model.

PURPOSE: We sought to develop a reproducible TGF-ß1 injection technique to induce urethral fibrosis in the rat urethra. MATERIALS AND METHODS: A total of 32 male Sprague Dawley® rats weighing 300 to 350 gm were anesthetized with ketamine/xylazine intraperitoneally. Using a 5 mm penoscrotal incision the rat urethra was exposed. In the experimental group varying doses of TGF-ß1 (5, 10 and 25 µg) were injected in each side of the urethral wall. Normal saline infiltration was used in the sham treated group. Rats were sacrificed 2 and 4 weeks following TGF-ß1 injection. Urethral specimens were stained with hematoxylin and eosin, and Masson trichrome, and Western blot evaluations were performed. Normal and strictured urethral tissues from patients were collected and evaluated in the same fashion. RESULTS: There was no evidence of urethral wall thickening or fibrosis in the sham treated group. Varied histological evidence of fibrosis was noted in all experimental groups. There was a significant increase in collagen type I expression 2 weeks after injection of 5, 10 and 25 µg TGF-ß1. Collagen type III expression was significantly increased 2 weeks after injecting 10 and 25 µg of TGF-ß1, which persisted to 28 days after injection. CONCLUSIONS: TGF-ß1 injection can successfully generate a reproducible rat model of urethral spongiofibrosis. This technique is simple, inexpensive and reproducible. Our series is a proof of concept study. Additional studies in larger animals are needed to further confirm our findings.

External urethral stenosis: a latent effect of sulfur mustard two decades post-exposure.

BACKGROUND: Sulfur mustard (SM), a chemical weapon used widely during World War I and against Iranians during the Iran-Iraq War of the 1980s, causes massive inflammatory tissue damage in the immediate post-exposure period, resulting in debilitating chronic disease in years to decades following contact with the agent. These syndromes most often are pathologies of the lungs, eyes, and skin, the primary target organs of SM. Typically, they are characterized by severe and increasingly painful inflammation, often accompanied by fibrosis and constriction of the anatomic channels needed for normal life, such as the small airways of the lungs and, in the present report, the urethra. METHODS: The present case study is a 43-year-old man with a history of heavy SM exposure to the groin in 1984. RESULT: Within 1 year after exposure, the patient was found to have developed meatal stricture, occlusion of the external urethral meatus, and difficulty in urination. Two years post-exposure, he underwent ventral meatotomy and meatoplasty. CONCLUSION: This case presents a unique example of the latent effects of SM exposure to the groin, and will be of value in the prevention of similar injury and complications to persons at risk of SM exposure in the future.

Urethral stricture following transurethral resection of the prostate. The role of local anaesthetics.

In a multicentre prospective study, 261 patients undergoing transurethral resection of the prostate (TURP) in 17 urology departments were randomised to receive lubricating jelly containing either 3% tetracaine hydrochloride, 1% lignocaine hydrochloride, or no local anaesthetic. No patient had a history of urethral instrumentation or a previous urethral stricture. After 6 months' follow-up, 25/79 patients (32%) treated with 3% tetracaine jelly developed urethral strictures, as did 4/92 patients (4%) who received 1% lignocaine and 2/90 (2%) who received the jelly without anaesthetic. It was concluded that the use of 3% tetracaine jelly is associated with a high incidence of post-TURP urethral strictures.

Effects of disopyramide on detrusor muscle contraction: in vitro experiment and report of 3 cases with disopyramide-induced urinary retention.

Three cases of disopyramide-induced urinary retention were reported and effects of disopyramide on agonist-induced contraction of detrusor muscle were studied in vitro. Muscle strips were obtained from rabbit bladder body and changes in isometric contraction of the strips were monitored. Acetylcholine, prostaglandin F2-alpha, potassium chloride, barium chloride, adenosine triphosphate and Ca2+ were used as agonists for detrusor muscle contraction. Disopyramide relaxed the contraction elicited by acetylcholine in normal Krebs solution, but exhibited no relaxing effect on contractions induced by prostaglandin F2-alpha, potassium chloride, barium chloride and adenosine triphosphate. In Ca2+-free Krebs solution, basal tension of the strips declined and spontaneous contractile activity was eliminated. Replenishment of 3 mM Ca2+ induced a slow contraction and redevelopment of spontaneous contraction of the strips. Pretreatment of the strips with disopyramide had no inhibitory effect on the Ca2+-induced contraction or on the spontaneous contractile activity in Ca2+-free solution. In normal Krebs solution, acetylcholine (10(-9)-10(-2)M) caused dose-dependent contractions of the detrusor muscle strips. Pretreatment of the strips with disopyramide (10(-5)-10(-3)M) dose-dependently inhibited the acetylcholine-induced contraction in a competitive way. The inhibitory effect of disopyramide on acetylcholine-induced contraction was less potent than that of atropine. We conclude that disopyramide may inhibit detrusor contractile activity mostly by its anticholinergic effect, resulting clinically in micturition disturbance.

Stricture of the anterior urethra following estrogen therapy in patients with prostatic cancer.

A high incidence of urethral strictures was noted in patients with prostatic cancer who were treated by antiandrogen therapy. Retrograde urethrograms showed urethral stricture in 24 of 42 patients (57%) after or during the therapy, despite the fact that no stricture was found before initiation of therapy. The stricture was long and the entire penile urethra was narrowed, associated with more severely constricted portions. All of the patients with urethral stricture had received estrogens, while none of the patients who had undergone castration alone or had not received any therapy showed a stricture. The strictures disappeared after the cessation of estrogen administration. These results indicate that estrogen administration induces stricture in the male anterior urethra. It is suggested that large amounts of estrogen cause atrophy and fibrosis of the spongy and cavernous bodies of the penis, depriving the urethra of its normal elasticity, which results in urethral stricture. The stricture is one of the complications of estrogen therapy for cancer of the prostate.

[Can silicon diffusion from silicone rubber catheters cause urethral stricture?]. / Kann eine Siliziumdiffusion aus Silikonkautschukkathetern Harnröhren-strikturen verursachen?

Silicon-leakage out of alloplastic Silicon containing implants induces myofibroblast proliferation and constricting scar tissue. Therefore the possible Silicon-leakage out of Silicon rubber Foley-Catheters was of major interest. This cathaters were often used after internal urethrotomies of recurrent urethral strictures. Pieces of Silicon rubber Foley-Catheters of 18 F, 2 cm in length, were implanted subcutaneously and intraperitoneally in rats. Using Scanning electron microscopy and EDXA (energy dispersiv x-ray microanalysis) Silicon could not be identified in tissues around the implants 6 and 12 weeks after implantation. Therefore Silicon-leakage out of Silicon rubber Foley-Catheters is not responsible for recurrent urethral strictures.

Urogenital tract abnormalities in sons of women treated with diethylstilbestrol.

Since in utero exposure to diethylstilbestrol (DES) is known to cause abnormalities of the female genital tract later in life, exposed male offspring were located, surveyed by mail, and compared with unexposed male offspring from the same period and medical practices. The exposed and unexposed respondents appeared comparable and did not differ in their response to most medical questions. However, a larger proportion of exposed than of unexposed boys had experienced problems in passing urine (12.9% vs. 1.8%, P = .0003) and abnormalities of the penile urethra (4.4% vs. 0%; P = .017).