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Schlagwörter:
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Zusammenfassung:
BACKGROUND & 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 cell numbers (F4/80(+)) or
alpha-smooth muscle actin expressing hepatic stellate cell numbers.
Further, there was no impact on TGF-beta or TNF-alpha. 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.
