Roxatidine inhibits fibrosis by inhibiting NF-κB and MAPK signaling in macrophages sensing breast implant surface materials

Capsular contracture is an important complication after silicone mammary implant surgery. Fibroblasts and macrophages play critical roles in the pathogenesis of capsular contracture, making these two cell types therapeutic targets. It has been reported that inhibiting histamine receptors results attenuates fibrosis, but the role of roxatidine (a histamine receptor 2 inhibitor) in preventing fibrosis caused by breast implant materials remains unknown. The aim of the present study was to assess the hypothesis that roxatidine might have a prophylactic effect in capsular contracture induced by implant material. Inflammation induced by breast implant materials was mimicked by co-culturing macrophages or fibroblasts with these materials in vitro. Capsular contracture was modeled in mice by planting breast implant materials in a subcutaneous pocket. Roxatidine was added in the culture medium or administered to mice bearing breast implant materials. By co-culturing macrophages or fibroblasts with common breast implant materials (micro-textured or smooth breast implants), the present study demonstrated that macrophages respond to these materials by producing pro-inflammatory cytokines, a process that was abolished by addition of roxatidine to the culture medium. Although fibroblasts did not respond to implant surface materials in the same way as macrophages, the conditioned media of macrophages induced proliferation of fibroblasts. Mechanistically, administration of roxatidine inhibited activation of NF-κB and p38/mitogen-activated protein kinase (MAPK) signaling in macrophages. Furthermore, treatment with roxatidine in implant-bearing mice reduced serum concentrations of transforming growth factor-β and the abundance of fibroblasts around the implant. The present study concluded that roxatidine plays an important role in preventing fibrosis by inhibiting activation of NF-κB and p38/MAPK signaling in macrophages.