Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic or advanced non-small cell lung cancer (NSCLC) whose tumors have specific EGFR mutations. Pulmonary toxicity is one of the fatal adverse effects of gefitinib and the underlying mechanism remains unclear. Here we demonstrated that alveolar macrophages contributed to gefitinib-induced pulmonary toxicity through promoting alveolar epithelial cells to undergo epithelial to mesenchymal transition (EMT) and inducing activation and antiapoptotic effect in fibroblasts. Further, we found that alveolar macrophage-secreted MCP-1 worked as a key factor in the pathologic changes of these two cell types. Gefitinib increased Mcp-1 transcription level via the nuclear import of the transcription factor STAT3. In conclusion, our data uncovered the underlying mechanisms of macrophage-promoted pulmonary toxicity in the presence of gefitinib. MCP-1 antibody or inhibition of STAT3 activation may represent novel therapeutic strategies for preventing gefitinib-induced pulmonary toxicity.

中文翻译：

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肺泡巨噬细胞和肺泡上皮细胞/成纤维细胞之间的串扰导致吉非替尼的肺毒性

吉非替尼是一种表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂，适用于肿瘤具有特定 EGFR 突变的转移性或晚期非小细胞肺癌 (NSCLC) 患者的一线治疗。肺毒性是吉非替尼的致命副作用之一，其潜在机制尚不清楚。在这里，我们证明肺泡巨噬细胞通过促进肺泡上皮细胞进行上皮间质转化 (EMT) 并诱导成纤维细胞的活化和抗凋亡作用，从而导致吉非替尼诱导的肺毒性。此外，我们发现肺泡巨噬细胞分泌的 MCP-1 是这两种细胞类型病理变化的关键因素。吉非替尼通过转录因子 STAT3 的核输入增加 Mcp-1 转录水平。总之，我们的数据揭示了在吉非替尼存在下巨噬细胞促进肺毒性的潜在机制。MCP-1 抗体或抑制 STAT3 激活可能代表预防吉非替尼诱导的肺毒性的新治疗策略。