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 trig...

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Published in:Science translational medicine 2012-05, Vol.4 (136), p.136ra71-136ra71
Main Authors: Yamaguchi, Yukie, Takihara, Takahisa, Chambers, Roger A, Veraldi, Kristen L, Larregina, Adriana T, Feghali-Bostwick, Carol A
Format: Article
Language:English
Subjects:
Animals
Bleomycin - pharmacology
Endostatins - chemistry
Fibrosis - chemically induced
Fibrosis - drug therapy
Humans
In Vitro Techniques
Male
Mice
Mice, Inbred C57BL
Peptides - chemistry
Peptides - therapeutic use
Protein-Lysine 6-Oxidase - metabolism
Pulmonary Fibrosis - chemically induced
Pulmonary Fibrosis - drug therapy
Skin - drug effects
Skin - metabolism
Skin - pathology
Transforming Growth Factor beta - pharmacology
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Summary: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.
ISSN:1946-6234
1946-6242
DOI:10.1126/scitranslmed.3003421