High regenerative capacity of the liver and irreversible injury of male reproductive system in carbon tetrachloride-induced liver fibrosis rat model
High regenerative capacity of the liver and irreversible injury of male reproductive system in carbon tetrachloride-induced liver fibrosis rat model
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DOI：
10.1007/s13167-017-0115-5
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发表时间：
2018-03-01
期刊：
影响因子：
6.5
通讯作者：
Gulko, Tamara P.
中科院分区：
文献类型：
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作者：
Bubnov, Rostyslav V.;Drahulian, Maria V.;Gulko, Tamara P.
研究背景肝纤维化是一种慢性疾病，与包括生殖功能障碍在内的多种伴发疾病相关。尽管正常肝脏有很大的再生能力，但肝功能衰竭的并发症可能是严重的和不可逆转的。Lf发育的激素和性相关问题以及与雄性生殖的相互作用还没有得到最终的研究。为研究实验性CCl4肝纤维化模型雄性大鼠的生殖功能，以及对肝脏和雄性生殖系统的恢复能力。实验动物注射新鲜配制的50%四氯化碳(CCl4)橄榄油溶液。注射后第8周观察肝纤维化表现。大鼠肝脏自愈8周。所有雄性大鼠分别于第8周和第16周进行肝脏和睾丸的超声检查和活检。雄性大鼠在注射CCl4前、造模后第8周和肝脏自愈后与健康雌性大鼠交配。结果实验第8周观察到晚期肝纤维化的超声表现，包括肝脾肿大、门脉高压。超声检查显示大鼠睾丸变性、鞘膜积液、纤维化、瘢痕形成、僵化、体积缩小、睾丸下降受限，睾丸大小由1.24±0.62毫升缩小至0.61±0.13毫升，p<；肝组织学表现为肝细胞颗粒状营养不良，坏死区，实质内有脂质包涵体。肝纤维化大鼠表现出严重的生殖系统损伤和生育能力改变：晚期肝功能衰竭雄性大鼠的后代活产4.71±-0.53，与健康雄性交配所生后代9.55+/-0.47，p<；0.001。在最后一次注射CCl4 8周后，我们发现了肝再生的迹象，其结构显著恢复。ALT和AST水平显著降低，达到本底水平。结论四氯化碳可引起肝实质损伤，引起快速、严重的肝纤维化，并与睾丸结构和功能发生不可逆性改变，降低生育力，降低潜在妊娠率，影响其发育。肝脏显示出很高的再生潜力，但肝纤维化后的自我修复并不伴随着生殖系统的恢复。
Background Liver fibrosis (LF) is a chronic disease, associated with many collateral diseases including reproductive dysfunction. Although the normal liver has a large regenerative capacity the complications of LF could be severe and irreversible. Hormone and sex-related issues of LF development and interactions with male reproductive have not been finally studied. The aim was to study the reproductive function of male rats in experimental CCl4-induced liver fibrosis rat model, and the capability for restoration of both the liver and male reproduction system.Materials Studies were conducted on 20 3-month old Wistar male rats. The experimental animals were injected with freshly prepared 50% olive oil solution of carbohydrate tetrachloride (CCl4). On the 8th week after injection we noted the manifestations of liver fibrosis. The rats were left to self-healing of the liver for 8 weeks. All male rats underwent ultrasound and biopsy of the liver and testes on the 8th and 16th weeks. The male rats were mated with healthy females before CCl4 injection, after modeling LF on the 8th week, and after self-healing of the liver. Pregnancy was monitored on ultrasound.Results On the 8th week of experiment we observed ultrasound manifestation of advanced liver fibrosis, including hepatosplenomegaly, portal hypertension. Ultrasound exam of the rat testes showed testicular degeneration, hydrocele, fibrosis, scarring, petrifications, size reduction, and restriction of testicular descent; testes size decreased from 1.24 +/- 0.62 ml to 0.61 +/- 0.13, p < 0.01. Liver histology showed granular dystrophy of hepatocytes, necrotic areas, lipid inclusions in parenchyma. Rats with liver fibrosis demonstrated severe injury of the reproductive system and altering of fertility: the offspring of male rats with advanced LF was 4.71 +/- 0.53 born alive vs 9.55 +/- 0.47 born from mating with healthy males, p < 0.001. Eight weeks after last CCl4 injection, we revealed signs of liver regeneration, significant recovery of its structure. The ALT and AST levels significantly decreased and reached background measurements. As a result of the second interbreeding after liver self-healing no significant difference was found vs previous mating.Conclusion Carbohydrate tetrachloride induces injury of liver parenchyma evoking fast and severe liver fibrosis, and is associated with irreversible structural and functional changes in testes, reducing fertility, decreasing potential pregnancy rate, and affecting its development. Liver showed high potential to regenerate, however the self-restoring after liver fibrosis was not accompanied with recovery of the reproductive system.