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J Hepatol. 2014 Jun 16. pii: S0168-8278(14)00405-X. doi: 10.1016/j.jhep.2014.06.010. [Epub ahead of print]

Inhibition of fibronectin deposition improves experimental liver fibrosis.

Author information

  • 1Max-Planck Institute for Biochemistry, 82152 Martinsried, Germany; Institute for Immunology, University of Heidelberg, 69120 Heidelberg, Germany. Electronic address: eva.altrock@immu.uni-heidelberg.de.
  • 2Max-Planck Institute for Biochemistry, 82152 Martinsried, Germany; Institute for Immunology, University of Heidelberg, 69120 Heidelberg, Germany. Electronic address: carla.sens@immu.uni-heidelberg.de.
  • 3Max-Planck Institute for Biochemistry, 82152 Martinsried, Germany; Institute for Immunology, University of Heidelberg, 69120 Heidelberg, Germany. Electronic address: carina.wuerfel@immu.uni-heidelberg.de.
  • 4Max-Planck Institute for Biochemistry, 82152 Martinsried, Germany; Institute for Immunology, University of Heidelberg, 69120 Heidelberg, Germany. Electronic address: matthaeusvasel@hotmail.de.
  • 5Max-Planck Institute for Biochemistry, 82152 Martinsried, Germany; Institute for Immunology, University of Heidelberg, 69120 Heidelberg, Germany. Electronic address: n.kawelke@gmx.de.
  • 6Department of Medicine I, University of Heidelberg at Mannheim, 68167 Mannheim, Germany. Electronic address: Steven.Dooley@medma.uni-heidelberg.de.
  • 7Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA. Electronic address: Jane_Sottile@URMC.Rochester.edu.
  • 8Max-Planck Institute for Biochemistry, 82152 Martinsried, Germany; Institute for Immunology, University of Heidelberg, 69120 Heidelberg, Germany. Electronic address: inaam.nakchbandi@urz.uni-heidelberg.de.

Abstract

BACKGROUND AND AIMS:

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 (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 the 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.

Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

Collagen; Extracellular; Fibril; Fibrogenesis; Fibronectin; Inhibition; Matrix

PMID:
24946284
[PubMed - as supplied by publisher]
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