Resolvin E3 reduces profibrotic factor production from macrophages leading to tissue homeostasis

Introduction: Organ fibrosis, characterized by ECM accumulation, is an abnormal tissue repair process and causes organ dysfunction leading to death. Pulmonary fibrosis remains intractable because no treatment can reverse its progression indefinitely. This is because many factors contribute to a complicated network as part of the fibrotic process in vivo. The resolvin E series (RvE), an anti-inflammatory and pro-resolution lipid mediator has been reported as a potential therapy for several diseases. However, the effect of RvEs on fibrogenesis and its detailed mechanism are not yet well-understood. Aims: This study aimed to evaluate the effect of RvE treatment in fibrosis in a bleomycin(BLM)-induced mouse model and the murine monocyte/macrophage cell line, RAW264.7. Methods: First, we administered BLM subcutaneously using osmotic pumps with 2µg/day RvE intraperitoneally for 5 days consecutively from day 0 to 8-week-old female C57BL/6J mice. We measured cell differentiation in BALF and several gene expressions in lung tissue at day 14. Second, we measured the concentration of profibrotic factors in supernatants from RAW264.7 cells after 100nM RvE treatment under LPS exposure. Results: In the murine BLM/RvE3 group, we found that macrophages in BALF, TGF-β1 mRNA, and CTGF mRNA were significantly decreased compared with other groups. Furthermore, in the RAW264.7 cells, RvE3 markedly reduced IL-1β and TGF-β1 production compared with other RvEs. Conclusions: These data indicate that macrophages are key contributors and that RvE3 attenuates fibrosis via its action on macrophage during the resolution stage. RvE3 may have the most significant advantage of improving fibrosis in RvEs.