Diminished induction of skin fibrosis in mice with MCP-1 deficiency.
Scar and fibrosis are often the end result of mechanical injury and inflammatory diseases. One chemokine that is repeatedly linked to fibrotic responses is monocyte chemoattractant protein-1 (MCP-1). We utilized a murine fibrosis model that produces dermal lesions similar to scleroderma to evaluate collagen fibrillogenesis in the absence of MCP-1. Dermal fibrosis was induced by subcutaneous injection of bleomycin into the dorsal skin of MCP-1-/- and wild-type C57BL/6 mice. After 4 weeks of daily injections, bleomycin treatment led to thickened collagen bundles with robust inflammation in the lesional dermis of wild-type mice. In contrast, the lesional skin of MCP-1-/- mice exhibited a dermal architecture similar to phosphate-buffered saline (PBS)-injected control and normal skin, with few inflammatory cells. Ultrastructural analysis of the lesional dermis from bleomycin-injected wild-type mice revealed markedly abnormal arrangement of collagen fibrils, with normal large diameter collagen fibrils replaced by small collagen fibrils of 41.5 nm. In comparison, the dermis of bleomycin-injected MCP-1-/- mice displayed a uniform pattern of fibril diameters that was similar to normal skin (average diameter 76.7 nm). The findings implicate MCP-1 as a key determinant in the development of skin fibrosis induced by bleomycin, and suggest that MCP-1 may influence collagen fiber formation in vivo.
Ferreira
Ahalia M
AM
Department of Surgery, The Burn and Shock Trauma Institute, Loyola University Medical Center, Maywood, Illinois, USA.
Takagawa
Shinsuke
S
Fresco
Raoul
R
Zhu
Xiaofeng
X
Varga
John
J
DiPietro
Luisa A
LA
D000818:Animals; D000964:Antimetabolites, Antineoplastic; D001761:Bleomycin; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D017364:Collagenases / Q000378:metabolism; D058575:Decorin; D020405:Dermis / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005347:Fibroblasts / Q000473:pathology / Q000648:ultrastructure; D000071235:Fibromodulin; D005355:Fibrosis; D015870:Gene Expression; D050958:HSP47 Heat-Shock Proteins / Q000235:genetics; D053509:Matrix Metalloproteinase 13; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011509:Proteoglycans / Q000235:genetics; D012871:Skin Diseases / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D000964:Antimetabolites, Antineoplastic; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; C000604332:Fmod protein, mouse; D050958:HSP47 Heat-Shock Proteins; D011509:Proteoglycans; C494661:Serpinh1 protein, mouse; C508961:Tgfb1 protein, mouse; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D000071235:Fibromodulin; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse