药物毒性研究中应激导致的多器官组织病理学变化的探讨

发布时间：2018-08-11 10:14

【摘要】：目的:以静脉给予食蟹猴抗表皮生长因子受体(anti-EGFR)单克隆抗体长期毒性研究作为个案分析,探讨药物毒性研究中应激反应造成多器官损伤的组织病理学特征。方法:将食蟹猴随机分为4组,分别为溶媒对照组、低剂量组、中剂量组和高剂量组。静脉推注给予EGFR单抗,每周1次,连续26周,停药后8周的恢复期。中高剂量组因动物状态差处于濒死状态而提前至给药22周解剖,进入恢复期。本研究中10只动物在给药期间死亡,死亡动物和其余动物均进行解剖和组织病理学检查。通过免疫组织化学方法检查所有动物垂体的促肾上腺皮质激素(ACTH)的表达。结果:本实验中给药动物出现不同程度腹泻、稀便、皮肤发红、脱毛、脱屑、溃烂。死亡动物的免疫器官表现出明显萎缩,包括胸腺、脾脏、淋巴结中淋巴细胞数目减少。死亡的雌性动物子宫重量减低,组织病理学表现为子宫萎缩伴纤维组织增生。此外,中高剂量组死亡动物肾上腺表现为皮质束状带细胞肥大。中高剂量组动物垂体ACTH的表达明显高于溶媒对照组。结论:药物毒性研究中应激反应诱导的免疫器官的萎缩,可伴有肾上腺皮质束状带细胞肥大。采用权重法综合分析所有数据,并结合垂体促肾上腺皮质激素的检测,这对于辅助性鉴别诊断应激和直接免疫毒性具有一定的意义。
[Abstract]:Objective: to study the long term toxicity of monoclonal antibody against epidermal growth factor receptor (anti-EGFR) induced by intravenous administration of anti-epidermal growth factor receptor (anti-EGFR) in crab monkeys as a case study, and to investigate the histopathological characteristics of multiple organ damage caused by stress response in drug toxicity study. Methods: the monkeys were randomly divided into four groups: medium control group, low dose group, middle dose group and high dose group. EGFR McAb was given intravenously once a week for 26 weeks, 8 weeks after withdrawal. In the middle and high dose group, the animals were dissected for 22 weeks due to their poor state of state. In this study, 10 animals died during administration, and all the dead animals and other animals were examined by anatomy and histopathology. The expression of adrenocorticotropic hormone (ACTH) in pituitary of all animals was detected by immunohistochemical method. Results: diarrhea, dilute stool, redness, depilation, desquamation and ulceration were observed in this experiment. The immune organs of the dead animals showed significant atrophy, including a decrease in the number of lymphocytes in the thymus, spleen, and lymph nodes. The weight of the dead female uterus is reduced, and the histopathological features are uterine atrophy with fibrous tissue proliferation. In addition, the adrenal gland in the middle and high dose groups showed hypertrophy of cortical bundles. The expression of pituitary ACTH in the middle and high dose group was significantly higher than that in the solvent control group. Conclusion: the atrophy of immune organs induced by stress in the study of drug toxicity may be accompanied by hypertrophy of adrenal cortical bundles. The weight method was used to analyze all the data and combined with the detection of pituitary adrenocorticotropic hormone, which has a certain significance for the differential diagnosis of stress and direct immunotoxicity.
【作者单位】：中国食品药品检定研究院国家药物安全评价监测中心;神州细胞工程有限公司;
【基金】：国家“重大新药创制”科技重大专项资助项目(2015ZX09501007-004;2009ZX09102-216)
【分类号】：R96

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