title: Deletion of the chemokine receptor CCR2 attenuates foreign body reaction to implants in mice.
abstract: Subcutaneous implantation of synthetic materials and biomedical devices often induces abnormal tissue healing - the foreign body reaction - which impairs their function. Here we investigated the role of the chemokine receptor CCR2 in this reaction to subcutaneous implants in mice. We measured angiogenesis, inflammation and fibrogenesis induced by implantation, for 1, 4, 7 and 14days, of polyether-polyurethane sponges in mice with genetic deletion of CCR2 (KO) and WT mice. Blood flow was determined by dye diffusion and laser Doppler perfusion techniques. Cytokines (VEGF, TNF-α, CCL2, TGF-β1) were measured by ELISA. Histochemical methods were used to assess collagen deposition and macrophage-derived giant cells in the implants. Skin and implant blood flow was lower in CCR2 KO than in WT mice, as were other aspects of neo-vascularization of the implants. Neutrophil accumulation was increased in KO implants but macrophage accumulation was decreased. Implant content of CCL2 was higher in KO implants, but TGF-β1, collagen deposition and the number of foreign body giant cells were lower than in WT implants. Deletion of CCR2 decreased blood flow in normal skin and inhibited neo-vascularization, chronic inflammation and fibrogenesis in subcutaneous implants. The chemokine receptor CCR2 plays an important role in both normal skin and in the reaction elicited by subcutaneous implantation of a foreign body.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Campus Pampulha, Cx Post 468, CEP 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Pollyana R
authors.initials: PR
authors.lastname: Castro
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Campus Pampulha, Cx Post 468, CEP 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Suzane M
authors.initials: SM
authors.lastname: Marques
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Campus Pampulha, Cx Post 468, CEP 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Celso T R
authors.initials: CT
authors.lastname: Viana
authors.affiliation: Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Campus Pampulha, Cx Post 468, CEP 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Paula P
authors.initials: PP
authors.lastname: Campos
authors.affiliation: Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Campus Pampulha, Cx Post 468, CEP 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Mônica A N D
authors.initials: MA
authors.lastname: Ferreira
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Campus Pampulha, Cx Post 468, CEP 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Lucíola S
authors.initials: LS
authors.lastname: Barcelos
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Campus Pampulha, Cx Post 468, CEP 31270-901 Belo Horizonte, MG, Brazil. Electronic address: andrades@icb.ufmg.br.
authors.forename: Silvia P
authors.initials: SP
authors.lastname: Andrade
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity; D018932:Chemokine CCL2 / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005549:Foreign-Body Reaction / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D017353:Gene Deletion; D015726:Giant Cells / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D020556:Neutrophil Infiltration; D054390:Receptors, CCR2 / Q000172:deficiency* / Q000235:genetics; D012039:Regional Blood Flow; D012867:Skin / Q000098:blood supply*; D015503:Surgical Sponges; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D003094:Collagen
keywords: Angiogenesis; CCL2; CCR2; Chemokine; Fibrogenesis; Foreign body reaction; Giant Cells; Inflammation; Sponge implants; Wound healing