Figure 6.

Dabigatran promotes inflammation resolution dependent on ADAMs and ALOX15. (A) Mouse PMN was treated with PBS (control; CON), heparin (HEP, 3 U/mL), warfarin (WAR, 100 ng/mL) and dabigatran (DAB, 100 ng/mL) for 6 h, the apoptotic PMN was determined with flow cytometry. (B) After mouse BMDMs were pretreated with PBS (control; CON), heparin (HEP, 3 U/mL), warfarin (WAR, 100 ng/mL), dabigatran (DAB, 100 ng/mL), TMI-1 (10 µM), and baicalein (Bai, 10 µM) for 4 h, they were co-cultured with CFSE-labeled apoptotic MC38 cells at the ratio of 1:10 for 30 min, efferocytosis was performed with flow cytometry. (C) After mouse BMDMs were pretreated with PBS (control; CON), dabigatran (DAB, 100 ng/mL), or RvD5_{n-3 DPA} (10 nM) with or without Anti-GPR101 (1:100) or anti-ALX/FPR2 (1:100) for 4 h, then they were co-cultured with CFSE-labeled apoptotic MC38 cells at the ratio of 1:10 for 30 min, efferocytosis was performed with flow cytometry. *P < 0.05 and **P < 0.01 vs. control. ^#P <0.05; ^##P < 0.01 and ^###P < 0.001 vs. dabigatran. (D-F) C57BL/6J mice were challenged with zymosan (Zym, 1mg i.p.) and treated with PBS (control; CON), dabigatran (DAB, 200 µg/kg), TMI-1 (200 µg/kg) and baicalein (Bai, 10 mg/kg). Peritoneal numbers of PMN (D), monocytes and macrophages (E) at indicated intervals were counted and resolution indices were calculated (F). (G) C57BL/6J mice were challenged with zymosan (Zym, 1mg i.p.), at 12 hr post injection, PBS (control; CON), warfarin (WAR, 200 µg/kg), dabigatran (DAB, 200 µg/kg), heparin (HEP, 200 IU/mouse), TMI-1 (200 µg/kg) and baicalein (Bai, 10 mg/kg) were administrated i.p., the peritoneal exudates were collected for counting PMN numbers. Error bars represent mean ± S.E.M. *P < 0.05 and **P < 0.01 vs. control. ^#P < 0.05; ^##P < 0.01 and ^###P < 0.001 vs. dabigatran; ^&P < 0.05 and ^&&P < 0.01 vs. Anti-GPR101 control; ^@@P < 0.01 vs. Anti-ALX/FPR2 control. (H) Schematic of dabigatran dual function in inflammation resolution.