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.

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。皮肤毒性是在接受 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，我们分析了接受吉非替尼 2.5 mg、5.0 mg 或 10 mg/100 g/天治疗 4 周的 Brown Norway (BN) 大鼠的皮疹表型及其病理特征。我们发现吉非替尼治疗以剂量依赖性方式导致体重减轻、皮疹、瘙痒和脱发。我们还研究了皮肤病理学，发现动物模型显示表皮增厚，水分流失，角质形成细胞凋亡。免疫组织化学、流式细胞术和血液中单核细胞和白细胞的分析显示巨噬细胞浸润增加与吉非替尼在 BN 大鼠中诱导的皮肤毒性有关。最后，我们发现吉非替尼诱导的皮肤毒性与已知由活化巨噬细胞分泌的三种炎性细胞因子 TREM-1、CINC-2 和 CINC-3 显着相关。