Nagler A, Gofrit O, Ohana M, Pode D, Genina O, Pines M
Departments of Bone Marrow Transplantation and Urology, Hadassah University Hospital, Jerusalem and Institute of Animal Science, Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel.
J Urol. 2000 Nov;164(5):1776-80.
Urethral strictures are narrowing of the urethra caused by fibrosis due to excessive collagen production in response to an insult. We evaluated the effects of halofuginone, a potent inhibitor of collagen alpha1(I) gene expression, on experimentally induced urethral strictures in vivo and on rat urethral fibroblasts in vitro.
Applying coagulation current to the male rat urethra produced urethral strictures. Halofuginone was given to the animals for 7 days, starting on the day of stricture formation, either orally at 1 and 5 ppm in the diet or by injection of 0.03% halofuginone solution into the urethra. All rats were sacrificed on day 21. Collagen alpha1(I) gene expression was evaluated by in situ hybridization, collagen content by sirius red staining and urethral morphology by urethrogram.
Coagulation current produced reproducible strictures with a typical urethrogram appearance, which were associated with increases in collagen alpha1(I) gene expression and collagen content at the stricture site. Halofuginone injected into the urethra or orally at 5 ppm normalized the urethrogram and prevented increases in collagen alpha1(I) gene expression and collagen content. Halofuginone at a concentration of 10-8 M. inhibited the collagen secreted by fibroblasts derived from the rat male urethra, which was due to inhibition of the collagen alpha1(I) gene expression.
Halofuginone prevented stricture formation and may become an important mode of therapy in the prevention of restenosis during urethral stricture formation.
尿道狭窄是由于受到损伤后胶原蛋白过度产生导致纤维化而引起的尿道狭窄。我们评估了卤夫酮（一种胶原蛋白α1（I）基因表达的强效抑制剂）对体内实验性诱导的尿道狭窄以及体外大鼠尿道成纤维细胞的影响。
对雄性大鼠尿道施加凝固电流以产生尿道狭窄。从狭窄形成之日起，给动物服用卤夫酮7天，通过在饮食中添加1 ppm和5 ppm的卤夫酮进行口服给药，或者向尿道注射0.03%的卤夫酮溶液。所有大鼠在第21天处死。通过原位杂交评估胶原蛋白α1（I）基因表达，通过天狼星红染色评估胶原蛋白含量，通过尿道造影评估尿道形态。
凝固电流产生了具有典型尿道造影外观的可重复性狭窄，这与狭窄部位胶原蛋白α1（I）基因表达和胶原蛋白含量的增加相关。向尿道注射卤夫酮或以5 ppm的剂量口服可使尿道造影正常化，并防止胶原蛋白α1（I）基因表达和胶原蛋白含量增加。浓度为10 - 8 M的卤夫酮抑制了源自大鼠雄性尿道的成纤维细胞分泌的胶原蛋白，这是由于抑制了胶原蛋白α1（I）基因表达。
卤夫酮可预防狭窄形成，可能成为预防尿道狭窄形成过程中再狭窄的一种重要治疗方式。
