Toxicol Appl Pharmacol. 2015 Oct 15;288(2):152-60.
Liu X1, Fang S2, Liu H3, Wang X1, Dai X1, Yin Q1, Yun T1, Wang W2, Zhang Y2, Liao H3, Zhang W1, Yao H4, Chao J5.[expand title=”Show Affiliations”]
- Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
- Nine Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, China.
- Neurobiology Laboratory, New Drug Screening Centre, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
- Department of Pharmacology, Medical School of Southeast University, Nanjing, Jiangsu 210009, China.
- Department of Physiology, Medical School of Southeast University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected]
Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO2). Phagocytosis of SiO2 in the lung initiates an inflammatory cascade that results in fibroblast proliferation and migration and subsequent fibrosis. Clinical evidence indicates that the activation of alveolar macrophages by SiO2 produces rapid and sustained inflammation that is characterized by the generation of monocyte chemotactic protein 1 (MCP-1), which induces fibrosis. Pulmonary fibroblast-derived MCP-1 may play a critical role in fibroblast proliferation and migration.
METHODS AND RESULTS:
Experiments using primary cultured adult human pulmonary fibroblasts (HPF-a) demonstrated the following results: 1) SiO2 treatment resulted in the rapid and sustained induction of MCP-1 as well as the elevation of the CC chemokine receptor type 2 (CCR2) protein levels; 2) pretreatment of HPF-a with RS-102895, a specific CCR2 inhibitor, abolished the SiO2-induced increase in cell activation and migration in both 2D and 3D culture systems; and 3) RNA interference targeting CCR2 prevented the SiO2-induced increase in cell migration.
These data demonstrated that the up-regulation of pulmonary fibroblast-derived MCP-1 is involved in pulmonary fibroblast migration induced by SiO2. CCR2 was also up-regulated in response to SiO2, and this up-regulation facilitated the effect of MCP-1 on fibroblasts. Our study deciphered the link between fibroblast-derived MCP-1 and SiO2-induced cell migration. This finding provides novel insight into the potential of MCP-1in the development of novel therapeutic strategies for silicosis.
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