title: Inhibition of fibronectin deposition improves experimental liver fibrosis.
abstract: OBJECTIVE
  Common pathogenic steps in liver fibrosis are inflammation and accumulation of extracellular matrix proteins including collagen, which lead to disruption of tissue microarchitecture and liver dysfunction. Adequate fibronectin fibril formation is required for collagen matrix deposition in several cell types in vitro. We therefore hypothesized that preventing fibronectin fibril assembly will result in decreased collagen matrix accumulation, and hence diminish liver injury associated with fibrosis.
  
  
  METHODS
  In vitro studies on hepatic stellate cells and in vivo studies in mice were performed.
  
  
  RESULTS
  In vitro studies on hepatic stellate cells confirmed that a fibronectin assembly inhibitor, pUR4 diminishes the amount of both fibronectin and collagen, accumulating in the extracellular matrix, without affecting their production. Induction of fibrosis using CCl4 or DMN was therefore combined with pUR4-treatment. pUR4 normalized the amount of fibrotic tissue that accumulated with injury, and improved liver function. Specifically, pUR4-treatment decreased collagen accumulation, without changing its mRNA expression. Most interestingly, we did not detect any changes in Kupffer cell numbers (F4/80+) or α-smooth muscle actin expressing hepatic stellate cell numbers. Further, there was no impact on TGF-β or TNF-α. Thus, in line with the in vitro findings, decreased fibrosis is due to inhibition of matrix accumulation and not a direct effect on these cells.
  
  
  CONCLUSIONS
  In summary, a peptide that blocks fibronectin deposition results in decreased collagen accumulation and improved liver function during liver fibrogenesis. Thus, fibronectin matrix modulation offers a therapeutic benefit in preclinical models of liver fibrosis.
authors.affiliation: Max-Planck Institute for Biochemistry, Martinsried, Germany; Institute for Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Altrock
authors.affiliation: Max-Planck Institute for Biochemistry, Martinsried, Germany; Institute for Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Carla
authors.initials: C
authors.lastname: Sens
authors.affiliation: Max-Planck Institute for Biochemistry, Martinsried, Germany; Institute for Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Wuerfel
authors.affiliation: Max-Planck Institute for Biochemistry, Martinsried, Germany; Institute for Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Matthaeus
authors.initials: M
authors.lastname: Vasel
authors.affiliation: Max-Planck Institute for Biochemistry, Martinsried, Germany; Institute for Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Kawelke
authors.affiliation: Department of Medicine I, University of Heidelberg at Mannheim, Mannheim, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Sottile
authors.affiliation: Max-Planck Institute for Biochemistry, Martinsried, Germany; Institute for Immunology, University of Heidelberg, Heidelberg, Germany. Electronic address: inaam.nakchbandi@immu.uni-heidelberg.de.
authors.forename: Inaam A
authors.initials: IA
authors.lastname: Nakchbandi
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005353:Fibronectins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D005353:Fibronectins; D050505:Mutant Proteins; D010455:Peptides; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D003094:Collagen
keywords: Collagen; Extracellular; Fibril; Fibrogenesis; Fibronectin; Inhibition; Matrix