A peptide derived from endostatin ameliorates organ fibrosis.
Fibroproliferative disorders such as idiopathic pulmonary fibrosis and systemic sclerosis have no effective therapies and result in significant morbidity and mortality due to progressive organ fibrosis. We examined the effect of peptides derived from endostatin on existing fibrosis and fibrosis triggered by two potent mediators, transforming growth factor-β (TGF-β) and bleomycin, in human and mouse tissues in vitro, ex vivo, and in vivo. We identified one peptide, E4, with potent antifibrotic activity. E4 prevented TGF-β-induced dermal fibrosis in vivo in a mouse model, ex vivo in human skin, and in bleomycin-induced dermal and pulmonary fibrosis in vivo, demonstrating that E4 exerts potent antifibrotic effects. In addition, E4 significantly reduced existing fibrosis in these preclinical models. E4 amelioration of fibrosis was accompanied by reduced cell apoptosis and lower levels of lysyl oxidase, an enzyme that cross-links collagen, and Egr-1 (early growth response gene-1), a transcription factor that mediates the effects of several fibrotic triggers. Our findings identify E4 as a peptide with potent antifibrotic activity and a possible therapeutic agent for organ fibrosis.
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Scleroderma Center, and Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Yukie
Y
Yamaguchi
Takahisa
T
Takihara
Roger A
RA
Chambers
Kristen L
KL
Veraldi
Adriana T
AT
Larregina
Carol A
CA
Feghali-Bostwick
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D043169:Endostatins / Q000737:chemistry*; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000737:chemistry* / Q000627:therapeutic use*; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D043169:Endostatins; D010455:Peptides; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D008249:Protein-Lysine 6-Oxidase