title: An endostatin-derived peptide orally exerts anti-fibrotic activity in a murine pulmonary fibrosis model.
abstract: OBJECTIVE
  Pulmonary fibrosis causes high morbidity and mortality in affected individuals. Recently, we showed that parenteral or intratracheal administration of a peptide derived from endostatin, called E4, prevents and ameliorates fibrosis using different models of dermal and pulmonary disease. No marketed orally delivered peptide drugs are currently available for progressive pulmonary fibrosis; however oral delivery of drugs is the preferred route for treating most chronic diseases. Thus, we investigated whether oral administration of E4 peptide exerted anti-fibrotic activity in a murine pulmonary fibrosis model.
  
  
  METHODS
  Bleomycin (1.2mU/g body weight) was intratracheally administrated to male 6-8-week-old C57BL/6J mice. E4 peptide (20, 10, 5, and 1 μg/mouse) or scrambled control peptide (20 μg/mouse) was orally administered on the same day as bleomycin. In some experiments, E4 peptide (10 and 5 μg/mouse) was orally administered three times on days 0, 3, and 6 post-bleomycin treatment. Lungs were harvested on day 21 for histological analysis and hydroxyproline assay.
  
  
  RESULTS
  Histological analysis and hydroxyproline assay revealed that bleomycin successfully induced pulmonary fibrosis, and that 20 μg of oral E4 peptide ameliorated the fibrosis. The lower doses of E4 peptide (10, 5, and 1 μg) were insufficient to exert anti-fibrotic activity when given as a single dose. Multiple doses of E4 peptide efficiently exerted anti-fibrotic activity even at lower doses.
  
  
  CONCLUSIONS
  E4 peptide shows oral bioavailability and exerts anti-fibrotic activity in a bleomycin-induced pulmonary fibrosis model. We suggest that E4 peptide is a novel oral drug for fibroproliferative disorders.
authors: Division of Rheumatology & Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors: Tetsuya
authors: T
authors: Nishimoto
authors: Division of Rheumatology & Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors: Logan
authors: L
authors: Mlakar
authors: Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan.
authors: Takahisa
authors: T
authors: Takihara
authors: Division of Rheumatology & Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA. Electronic address: feghalib@musc.edu.
authors: Carol
authors: C
authors: Feghali-Bostwick
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage; D004195:Disease Models, Animal; D043169:Endostatins / Q000008:administration & dosage*; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000008:administration & dosage*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D010446:Peptide Fragments; D001761:Bleomycin; D006909:Hydroxyproline
keywords: Endostatin; Oral administration; Pulmonary fibrosis