南方医科大学学报

南方医科大学学报 ›› 2022, Vol. 42 ›› Issue (3): 411-417.doi: 10.12122/j.issn.1673-4254.2022.03.14

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吡非尼酮通过抑制TGF-β1通路和炎症反应预防大鼠尿道损伤后的纤维化及狭窄

李 中，黄 旭，陈守峰，张智健，梁 心，李海慧，秦 雷，郭园园   

  1. 蚌埠医学院第一附属医院泌尿外科，胸心外科，放射科，安徽 蚌埠 233040；蚌埠医学院临床医学院，安徽 蚌埠 233040
  • 出版日期:2022-03-20 发布日期:2022-04-12

Pirfenidone alleviates urethral stricture following urethral injury in rats by suppressing TGF-β1 signaling and inflammatory response

LI Zhong, Huang Xu, CHEN Shoufeng, ZHANG Zhijian, LIANG Xin, LI Haihui, QIN Lei, GUO Yuanyuan   

  1. Department of Urology, Department of Cardiothoracic Surgery, Department of Radiology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233040, China; School of Clinical Medicine, Bengbu Medical College, Bengbu 233040, China
  • Online:2022-03-20 Published:2022-04-12

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摘要： 目的 探讨吡非尼酮对大鼠尿道损伤后狭窄形成的预防作用及可能机制。方法 选取SD雄性大鼠30只，随机分为3组（10只/组）：阴性对照组、阳性对照组及吡非尼酮组。吡非尼酮组：切开后尿道海绵体建立大鼠尿道损伤模型，按100 mg·kg-1·d-1腹腔注射吡非尼酮；模型组：同对照组构建大鼠尿道损伤模型，腹腔注射等量溶剂；假手术组：不予尿道损伤处理，但腹腔注射等量溶剂。术后2周逆行尿道造影观察尿道狭窄，留取尿道损伤组织，行HE染色观察尿道组织形态学变化，Masson染色检测胶原变化，免疫组化及Western blot检测a-SMA和TGF-β1的蛋白表达，qRT-PCR检测大鼠尿道组织中炎症因子TNF-α、IL-6、IL-1βmRNA的表达。结果 吡非尼酮组大鼠较阴性对照和阳性对照组体质量下降，逆行尿道造影显示阳性对照组大鼠尿道显著变窄，吡非尼酮组大鼠尿道较阳性对照组大鼠明显好转（P<0.05）。HE染色显示阳性对照组尿道上皮细胞增生，管腔狭窄，炎性细胞增多；吡非尼酮组病理学表现与阴性对照组相似。Masson染色显示吡非尼酮组较阳性对照组胶原纤维含量少，排列规则有序。免疫组化和Western blot结果表明阳性对照组尿道a-SMA和TGF-β1表达显著高于阴性对照组（P<0.05，P<0.01），而吡非尼酮能够抑制TGF-β1和α-SMA的表达。qRT-PCR结果显示吡非尼酮能够抑制损伤组织中TNF-α、IL-6、IL-1β等炎症因子的基因表达（P<0.05，P<0.01）。结论 吡非尼酮可预防尿道损伤后纤维化及狭窄，并可能与抑制TGF-β1通路和炎症反应相关。

关键词: 吡非尼酮；尿道狭窄；纤维化；炎症；TGF-β1

Abstract: Objective To investigate the effect of pirfenidone for reducing urethral stricture following urethral injury in rats and explore the possible mechanism. Methods Thirty male SD rats were randomly assigned into negative control group, positive control group and pirfenidone group (n=10). In pirfenidone and positive control groups, the rats were subjected to incision of the posterior urethral cavernous body followed by daily intraperitoneal injection of pirfenidone (100 mg/kg) and an equivalent volume of solvent, respectively. The rats in the negative control group were given intraperitoneal injections of solvent without urethral injury. At two weeks after modeling, retrograde urethrography was performed for observing urethral stricture, and the injured urethral tissues were harvested for HE staining, Masson staining, immunohistochemical staining and Western blotting for detecting the protein expressions of α-SMA and TGF-β1. The mRNA expressions of the inflammatory factors TNF-α, IL-6, and IL-1β were detected using qRT-PCR. Results The body weight of the rats in pirfenidone group was significantly decreased compared with that in the other two groups (P<0.05). Retrograde urethrography showed significant narrowing of the urethra in the positive control group but not in the pirfenidone group. HE staining of the injured urethral tissues showed obvious proliferation of urethral epithelial cells with narrow urethral cavity and increased inflammatory cells in positive control group. The pathological findings of the urethra were similar between pirfenidone group and the negative control group. Masson staining revealed obviously reduced collagen fibers and regular arrangement of the fibers in pirfenidone group as compared to the positive control group. Compared with those in the negative control group, the expressions of α-SMA and TGF-β1 were significantly increased in the positive control group, and pirfenidone treatment significantly inhibited their expressions (P<0.05 or 0.01). Pirfenidone also significantly inhibited the mRNA expressions of TNF-α, IL-6, and IL-1β in the injured urethral tissue (P<0.05 or 0.01). Conclusion Pirfenidone can prevent urethral fibrosis and stricture after urethral injury possibly by inhibiting the TGF-β1 pathway and inflammatory response.

Key words: pirfenidone; urethra stricture; fibrosis; inflammation; transforming growth factor-β1