Gefitinib-Induced Cutaneous Toxicities in Brown Norway Rats Are Associated with Macrophage Infiltration
Gefitinib-Induced Cutaneous Toxicities in Brown Norway Rats Are Associated with Macrophage Infiltration
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DOI：
10.1007/s10753-020-01281-2
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发表时间：
2020-10-06
期刊：
影响因子：
5.1
通讯作者：
Hua, Qian
中科院分区：
文献类型：
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作者：
Wan, Liangqin;Wang, Yalei;Hua, Qian
吉非替尼（易瑞沙）是一种选择性表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），用于局部晚期或转移性非小细胞肺癌（NSCLC）的靶向治疗。皮肤毒性是接受 EGFR 靶向 TKI（如吉非替尼和厄洛替尼）治疗的患者中观察到的主要不良反应。迄今为止，尚未建立相应的皮肤动物模型来解决这些影响的机制。因此，我们分析了用吉非替尼 2.5 mg、5.0 mg 或 10 mg/100 g/天治疗 4 周的挪威布朗 (BN) 大鼠的皮疹表型及其病理特征。我们发现吉非替尼治疗会导致体重减轻、皮疹、瘙痒和脱发，且呈剂量依赖性。我们还研究了皮肤病理学，发现动物模型表现出表皮增厚、水分流失和角质形成细胞凋亡。免疫组织化学、流式细胞术以及血液中单核细胞和白细胞的分析表明，巨噬细胞浸润增加与吉非替尼在 BN 大鼠中引起的皮肤毒性有关。最后，我们发现吉非替尼引起的皮肤毒性与已知由活化巨噬细胞分泌的三种炎症细胞因子 TREM-1、CINC-2 和 CINC-3 显着相关。
Gefitinib (Iressa), is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), used in the targeted treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). Skin toxicity is the major adverse effect observed in patients treated with EGFR-targeted TKIs such as gefitinib and erlotinib. To date, a corresponding skin animal model has not been established to address the mechanisms of these effects. Therefore, we analyzed the skin rash phenotype and its pathological features in Brown Norway (BN) rats treated with gefitinib 2.5 mg, 5.0 mg, or 10 mg/100 g/day for 4 weeks. We found that treatment with gefitinib led to weight loss, rash, itching, and hair loss in a dose-dependent manner. We also investigated the skin pathology and found that the animal model showed thickening of the epidermis, loss of moisture, and apoptosis of keratinocytes. Immunohistochemistry, flow cytometry, and analysis of monocytes and leukocytes in the blood revealed increased macrophage infiltration was associated with the cutaneous toxicities induced by gefitinib in the BN rats. Finally, we found that gefitinib-induced cutaneous toxicity is significantly associated with three inflammatory cytokines known to be secreted by activated macrophages, TREM-1, CINC-2, and CINC-3.