cangrelor and Inflammation

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.

Topics: Adenosine Monophosphate; Animals; Bleomycin; Cell Survival; Dose-Response Relationship, Drug; Inflammation; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Pulmonary Fibrosis; RAW 264.7 Cells; Receptors, G-Protein-Coupled; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Essentials The role of platelet P2Y. Background P2Y

Topics: Adenosine Monophosphate; Aniline Compounds; Animals; Blood Platelets; Chemokine CXCL1; Chronic Pain; Cytokines; Freund's Adjuvant; Furans; Hyperalgesia; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pain; Receptors, Purinergic P2Y12; Time Factors; Tumor Necrosis Factor-alpha