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• Macrophages contribute to gefitinib-induced pulmonary toxicity. • Macrophage-secreted MCP-1 is a key mediator of gefitinib-induced pulmonary toxicity. • MCP-1 promotes alveolar epithelial cells to undergo EMT. • MCP-1 participates in gefinitib-induced activation and antiapoptosis in fibroblasts. • Gefitinib increases Mcp-1 transcription level via the nuclear import of STAT3. 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. [ABSTRACT FROM AUTHOR]