Relaxin decreases the severity of established hepatic fibrosis in mice.

Abstract

BACKGROUND & AIMS:

Hepatic fibrosis is characterized by excess collagen deposition, decreased extracellular matrix degradation and activation of the hepatic stellate cells. The hormone relaxin has shown promise in the treatment of fibrosis in a number of tissues, but the effect of relaxin on established hepatic fibrosis is unknown. The aim of this study was to determine the effect of relaxin on an in vivo model after establishing hepatic fibrosis

METHODS:

Male mice were made fibrotic by carbon tetrachloride treatment for 4 weeks, followed by treatment with two doses of relaxin (25 or 75 μg/kg/day) or vehicle for 4 weeks, with continued administration of carbon tetrachloride.

RESULTS:

Relaxin significantly decreased total hepatic collagen and smooth muscle actin content at both doses, and suppressed collagen I expression at the higher dose. Relaxin increased the expression of the matrix metalloproteinases MMP13 and MMP3, decreased the expression of MMP2 and tissue inhibitor of metalloproteinase 2 (TIMP2) and increased the overall level of collagen-degrading activity. Relaxin decreased TGFβ-induced Smad2 nuclear localization in mouse hepatic stellate cells.

CONCLUSIONS:

The results suggest that relaxin reduced collagen deposition and HSC activation in established hepatic fibrosis despite the presence of continued hepatic insult. This reduced fibrosis was associated with increased expression of the fibrillar collagen-degrading enzyme MMP13, decreased expression of TIMP2, and enhanced collagen-degrading activity, and impaired TGFβ signalling, consistent with relaxin's effects on activated fibroblastic cells. The results suggest that relaxin may be an effective treatment for the treatment of established hepatic fibrosis.

• Authors: Robert G Bennett, Dean G Heimann, Sudhir Singh, Ronda L Simpson, Dean J Tuma
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 34 Issue 3 Pg. 416-26 (Mar 2014) ISSN: 1478-3231 [Electronic] United States
• PMID: 23870027 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Chemical References

• Actins
• Smad2 Protein
• Smad2 protein, mouse
• Transforming Growth Factor beta
• alpha-smooth muscle actin, mouse
• Tissue Inhibitor of Metalloproteinase-2
• Relaxin
• Collagen
• Carbon Tetrachloride
• Matrix Metalloproteinases, Secreted

Topics

• Actins (metabolism)
• Animals
• Carbon Tetrachloride (toxicity)
• Cells, Cultured
• Collagen (metabolism)
• Hepatic Stellate Cells (drug effects)
• Hepatocytes (metabolism)
• Liver (pathology)
• Liver Cirrhosis (drug therapy)
• Male
• Matrix Metalloproteinases, Secreted (metabolism)
• Mice
• Mice, Inbred C57BL
• Relaxin (therapeutic use)
• Smad2 Protein (metabolism)
• Tissue Inhibitor of Metalloproteinase-2 (metabolism)
• Transforming Growth Factor beta (metabolism)