南方医科大学学报

南方医科大学学报 ›› 2021, Vol. 41 ›› Issue (3): 352-357.doi: 10.12122/j.issn.1673-4254.2021.03.06

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表皮生长因子受体抑制剂相关皮疹动物模型的构建

张 旭，薛崇祥1，李 嘉，张静怡，谭可欣，姜雪娇，郑舒月，董慧静，俞仪萱，胡紫馨，崔慧娟   

  • 出版日期:2021-03-20 发布日期:2021-04-06

Establishment of animal models of epidermal growth factor receptor inhibitor-related rashes

  • Online:2021-03-20 Published:2021-04-06

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摘要： 目的 复制表皮生长因子受体抑制剂相关皮疹动物模型并进行进一步优化和探索。方法 应用西妥昔单抗注射液，按照20、40、80 mg/kg对雌性SCID小鼠进行腹腔注射，给药频次为每周一、三、五，共干预28 d。实验过程中持续关注小鼠皮肤形态学变化，在实验结束后对小鼠皮肤进行切片，观察HE染色表现。应用吉非替尼、厄洛替尼、卵清蛋白分别按照按照37.5 mg/kg、23.5 mg/kg、1 mg/只进行灌胃口服，1次/d，共给药45 d。实验过程中持续观察大鼠皮肤形态学变化，实验结束后对大鼠皮肤进行切片，观察HE染色表现。并应用ELISA法对大鼠血清中TNF-α、IL-6、IgE等因子进行测定。结果 西妥昔单抗腹腔注射后，SCID小鼠未出现典型的皮疹、结痂表现；皮肤病理未显示出明显的炎症表现。吉非替尼组大鼠皮肤可见明显的皮疹、结痂、渗出等表现，且皮肤HE染色可见大量的炎症细胞浸润、角化不全、棘层松解、表皮增厚等表现；空白组、卵清蛋白组、厄洛替尼组大鼠皮肤形态学观察及病理切片未见明显的炎症表现。在IgE、TNF-α浓度方面，各组间均未见明显差异（P=0.061，P=0.057）；而 在 IL-6 方面，吉非替尼组较空白组明显升高，差异具有统计学意义（P=0.016），而厄洛替尼组较空白组未见明显差异（P= 0.910）。结论 应用西妥昔单抗不能在SCID小鼠中建立表皮生长因子受体抑制剂相关皮疹模型。应用吉非替尼可以在BN大鼠中建立表皮生长因子受体抑制剂相关皮疹模型；应用厄洛替尼不能在BN大鼠中诱发皮疹。

关键词: 表皮生长因子受体抑制剂；皮疹；动物模型；SCID小鼠；BN大鼠

Abstract: Objective To establish animal models epidermal growth factor receptor inhibitor-related skin rashes using cetuximab, gefitinib or erlotinib. Methods Female SCID mice were randomly divided into blank control group and high- , moderate-, and low-dose cetuximab groups. The mice in control group received intraperitoneal injection of saline, and those in the 3 cetuximab groups were injected with 80, 40, and 20 mg/kg cetuximab (3 times a week for 4 weeks), respectively. The general skin appearance and skin pathologies of the mice were observed. Female BN rats were randomly divided into blank group, ovalbumin group, gefitinib group and erlotinib group, and in the latter 3 groups, the rats were given ovalbumin (1 mg), gefitinib (37.5 mg/kg), and erlotinib (23.5 mg/kg) by lavage once daily for 45 days, respectively. Skin pathologies of the rats were observed, and serum levels of TNF-α, IL-6 and other inflammatory factors were detected using ELISA. Results Intraperitoneal injection of cetuximab did not induce typical skin rashes, scabs or obvious skin inflammation in the mice. In female BN rats, lavage of gefitinib caused obvious skin rashes, scabs and exudation, and obvious inflammatory cell infiltration, keratinosis, spinous layer release and epidermal thickening were observed in the skin. No obvious skin inflammation were observed in the rats in the control, ovalbumin or erlotinib groups. While IgE (P=0.061) and TNF-α concentrations (P=0.057) did not differ significantly among the groups, serum levels of IL-6 was significantly higher in gefitinib group than in the blank control group (P=0.016) but similar between erlotinib group and the blank group (P=0.910). Conclusion Intraperitoneal injection of cetuxdimab can not induce epidermal growth factor receptor inhibitor-related skin rashes in SCID mice. Lavage of gefitinib, but not erlotinib, can be used to establish models of epidermal growth factor receptor inhibitor-related rashes in BN rats.

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