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Int Immunopharmacol. 2018 Sep;62:261-269. doi: 10.1016/j.intimp.2018.06.006. Epub 2018 Jul 23.

Cangrelor alleviates pulmonary fibrosis by inhibiting GPR17-mediated inflammation in mice.

Author information

1
Department of Thoracic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jie-Fang Road, Hangzhou, Zhejiang 310009, China.
2
Department of Pharmacology, Zhejiang University School of Medicine, 866 Yu-Hang-Tang Road, Hangzhou, Zhejiang 310058, China.
3
Department of Thoracic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jie-Fang Road, Hangzhou, Zhejiang 310009, China. Electronic address: iwuming22@zju.edu.cn.

Abstract

Pulmonary fibrosis is a progressive and intractable lung disease. Macrophages play a critical role in the progression of pulmonary fibrosis. Cangrelor, an anti-platelet agent, is also a non-selective Gprotein-coupled receptor 17 (GPR17) antagonist. GPR17 mediates microglial inflammation in the chronic phase of cerebral ischemia and regulates allergic pulmonary inflammation. In this study, we observed the effects of cangrelor on bleomycin (BLM)-induced macrophage cellular inflammation and BLM-induced pulmonary fibrosis in C57BL/6J mice. We found that BLM significantly increased GPR17 expression, the mRNA synthesis and release of inflammatory cytokines including TNF-α, IL-6 and TGF-β1 in murine RAW 264.7 macrophage cells. Knockdown of GPR17 attenuated the BLM-induced inflammatory responses. Cangrelor (2.5 μM-10 μM) significantly alleviated BLM-induced inflammatory response in RAW 264.7 macrophage cells in concentration-dependent manner. In BLM-induced fibrotic mouse lungs, GPR17 expression and GPR17-positive macrophages were increased. Cangrelor (2.5 mg/kg-10 mg/kg) alleviated pulmonary fibrosis in dose-dependent manner. Cangrelor not only reduced the number of GPR17-positive macrophages, but also decreased BLM-induced mRNA synthesis and release of inflammatory cytokine. As such, we concluded that cangrelor alleviates BLM-induced pulmonary fibrosis by suppressing GPR17-mediated inflammation. Cangrelor could be a potential therapeutic drug for pulmonary fibrosis.

KEYWORDS:

Cangrelor; GPR17; Inflammatory cytokines; Macrophages; Pulmonary fibrosis

PMID:
30036769
DOI:
10.1016/j.intimp.2018.06.006
[Indexed for MEDLINE]

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