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

Abstract

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.

Mycobacterium tuberculosis Utilizes Host Histamine Receptor H1 to Modulate Reactive Oxygen Species Production and Phagosome Maturation via the p38MAPK-NOX2 Axis

“…Ji et al ( 32 ) recently demonstrated that the HRH2 inhibitor roxatidine prevents fibrosis by inactivating the NF-κB and p38MAPK signaling pathways in macrophages. In addition, terfenadine, a selective chemical inhibitor of HRH1, was reported to enhance phosphor-p38MAPK levels in basal BC cells ( 33 ).…”

The Effect of Mesenchymal Stem Cells on Capsule Formation around Silicone Implant in Rats

“…38,39 In a recent study it was concluded that roxatidine played an important role in preventing fibrosis by inhibiting the activation of NF-κB and p38/mitogen-activated protein kinase (MAPK) signals in macrophages. 40 Kølle et al 41 reported that autologous adipose tissue grafts enriched with adipose tissue-derived stem cells had a longer life, less resorption and higher volume than nonenriched grafts in breast reconstruction surgery. However, the determination of the best adipose tissue source for the isolation of adipose tissue+derived stem cells, the means of maintaining mature adipose tissue volumes in breast reconstruction, the oncological safety of stem cell applications in patients with breast cancer due to the risk of cancer recurrence, the effects of adjuvant therapies on stem cell isolation and the associated effects on implant surgery have not been fully elucidated.…”

Silicone Implants Immobilized with Interleukin-4 Promote the M2 Polarization of Macrophages and Inhibit the Formation of Fibrous Capsules

“…Silicone implants immobilized with or without IL-4 were then placed on the cell culture plates. The silicone implants were capable of inducing biomaterial-mediated inflammation and activating macrophages, and lead to macrophage polarization [ 21 , 22 ].…”