Topical application of a peptide inhibitor of transforming growth factor-beta1 ameliorates bleomycin-induced skin fibrosis.
Transforming growth factor-beta (TGF-beta) plays a crucial role in the pathogenesis of skin fibrotic diseases. Systemic TGF-beta inhibitors effectively inhibit fibrosis in different animal models; however, systemic inhibition of TGF-beta raises important safety issues because of the pleiotropic physiological effects of this factor. In this study, we have investigated whether topical application of P144 (a peptide inhibitor of TGF-beta1) ameliorates skin fibrosis in a well-characterized model of human scleroderma. C3H mice received daily subcutaneous injections of bleomycin for 4 wk, and were treated daily with either a lipogel containing P144 or control vehicle. Topical application of P144 significantly reduced skin fibrosis and soluble collagen content. Most importantly, in mice with established fibrosis, topical treatment with P144 lipogel for 2 wk significantly decreased skin fibrosis and soluble collagen content. Immunohistochemical studies in P144-treated mice revealed a remarkable suppression of connective tissue growth factor expression, fibroblast SMAD2/3 phosphorylation, and alpha-smooth muscle actin positive myofibroblast development, whereas mast cell and mononuclear cell infiltration was not modified. These data suggest that topical application of P144, a peptide inhibitor of TGF-beta1, is a feasible strategy to treat pathological skin scarring and skin fibrotic diseases for which there is no specific therapy.
Santiago
Begoña
B
Unidad de Investigación, Hospital 12 de Octubre, Madrid, Spain.
Gutierrez-Cañas
Irene
I
Dotor
Javier
J
Palao
Guillermo
G
Lasarte
Juan José
JJ
Ruiz
Juan
J
Prieto
Jesús
J
Borrás-Cuesta
Francisco
F
Pablos
José L
JL
D000287:Administration, Topical; D000818:Animals; D001761:Bleomycin / Q000037:antagonists & inhibitors; D002921:Cicatrix / Q000188:drug therapy* / Q000378:metabolism; D004655:Emulsions; D005355:Fibrosis / Q000139:chemically induced; D005782:Gels; D051379:Mice; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000494:pharmacology*; D018125:Receptors, Transforming Growth Factor beta / Q000008:administration & dosage*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D053773:Transforming Growth Factor beta1
D004655:Emulsions; D005782:Gels; D010446:Peptide Fragments; D018125:Receptors, Transforming Growth Factor beta; C504795:TGF-beta1 type III receptor (730-743), human; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001761:Bleomycin