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亚氨基二丙腈诱导大鼠肝肾毒性的时间进程评估:一项生化、分子和组织病理学研究

Time-Course Evaluation of Iminodipropionitrile-Induced Liver and Kidney Toxicities in Rats: A Biochemical, Molecular and Histopathological Study.

作者信息

Alwelaie Manar A, Al-Mutary Mohsen G, Siddiqi Nikhat J, Arafah Maha M, Alhomida Abdullah S, Khan Haseeb A

机构信息

Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.

Department of Basic Sciences, College of Education, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.

出版信息

Dose Response. 2019 May 23;17(2):1559325819852233. doi: 10.1177/1559325819852233. eCollection 2019 Apr-Jun.

Abstract

Iminodipropionitrile (IDPN) is known to produce axonopathy and vestibular hair cell degeneration. Recent histopathological studies have shown IDPN-induced liver and kidney toxicities in rodents; however, the associated mechanisms are not clearly understood. We investigated the role of proinflammatory cytokines in IDPN-induced liver and kidney toxicities in rats. Rats were treated with saline (control) and IDPN (100 mg/kg, intraperitoneally) daily for 1, 5, and 10 days, respectively. Animals were killed 24 hours after the last dose and liver and kidneys were collected for histopathology and interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α messenger RNA expression analysis. Serum aspartate aminotransferase and alanine aminotransferase activities were significantly increased after 10 doses of IDPN. The level of serum creatinine was initially increased after the first dose of IDPN but subsided on days 5 and 10. Blood urea nitrogen levels were significantly increased on days 5 and 10 following IDPN exposure. Histopathology showed dose-dependent hepatotoxicity in IDPN-treated rats. Iminodipropionitrile-induced expression of proinflammatory cytokines peaked after day 1 in liver and after day 5 in kidneys. In conclusion, repeated exposure of IDPN for 10 days produced significant structural and functional damages in rat liver whereas kidneys showed gradual recovery with time. These findings point toward the role of inflammatory mediators in IDPN-induced toxicity in rats.

摘要

已知亚氨基二丙腈(IDPN)会导致轴索性神经病和前庭毛细胞变性。最近的组织病理学研究表明,IDPN会在啮齿动物中引发肝脏和肾脏毒性;然而,相关机制尚不清楚。我们研究了促炎细胞因子在IDPN诱导的大鼠肝脏和肾脏毒性中的作用。大鼠分别每天接受生理盐水(对照组)和IDPN(100 mg/kg,腹腔注射)处理,持续1天、5天和10天。在最后一次给药后24小时处死动物,收集肝脏和肾脏进行组织病理学检查以及白细胞介素-1β(IL-1β)、IL-6和肿瘤坏死因子-α信使核糖核酸表达分析。给予10次IDPN后,血清天冬氨酸氨基转移酶和丙氨酸氨基转移酶活性显著升高。首次给予IDPN后,血清肌酐水平最初升高,但在第5天和第10天有所下降。IDPN暴露后第5天和第10天,血尿素氮水平显著升高。组织病理学显示,IDPN处理的大鼠存在剂量依赖性肝毒性。IDPN诱导的促炎细胞因子表达在肝脏中于第1天后达到峰值,在肾脏中于第5天后达到峰值。总之,重复暴露于IDPN 10天会在大鼠肝脏中产生显著的结构和功能损伤,而肾脏则随时间逐渐恢复。这些发现表明炎症介质在IDPN诱导的大鼠毒性中起作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ea1f/6537673/1ef21ace0bfc/10.1177_1559325819852233-fig1.jpg

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