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  • Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo

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Liver disease
Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo
  1. E J Williamsa,
  2. R C Benyona,
  3. N Trima,
  4. R Hadwina,
  5. B H Groveb,
  6. M J P Arthura,
  7. E N Unemorib,
  8. J P Iredalea
  1. aLiver Research Group, Division of Cell and Molecular Medicine, D Level, South Academic Block, Southampton General Hospital, Southampton, UK, bConnetics Corporation, Palo Alto, CA, USA
  1. J Iredale, Liver Research Group, Division of Cell and Molecular Medicine, Mail Point 811, Southampton General Hospital, Southampton SO16 6YD, UK. jpi{at}soton.ac.uk

Abstract

BACKGROUND Following liver injury, hepatic stellate cells (HSC) transform into myofibroblast-like cells (activation) and are the major source of type I collagen and the potent collagenase inhibitors tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and TIMP-2) in the fibrotic liver. The reproductive hormone relaxin has been reported to reduce collagen and TIMP-1 expression by dermal and lung fibroblasts and thus has potential antifibrotic activity in liver fibrosis.

AIMS To determine the effects of relaxin on activated HSC.

METHODS Following isolation, HSC were activated by culture on plastic and exposed to relaxin (1–100 ng/ml). Collagen deposition was determined by Sirius red dye binding and radiolabelled proline incorporation. Matrix metalloproteinase (MMP) and TIMP expression were assessed by zymography and northern analysis. Transforming growth factor β1 (TGF-β1) mRNA and protein levels were quantified by northern analysis and ELISA, respectively.

RESULTS Exposure of activated HSC to relaxin resulted in a concentration dependent decrease in both collagen synthesis and deposition. There was a parallel decrease in TIMP-1 and TIMP-2 secretion into the HSC conditioned media but no change in gelatinase expression was observed. Northern analysis demonstrated that primary HSC, continuously exposed to relaxin, had decreased TIMP-1 mRNA expression but unaltered type I collagen, collagenase (MMP-13), alpha smooth muscle actin, and TGF-β1 mRNA expression.

CONCLUSION These data demonstrate that relaxin modulates effective collagen deposition by HSC, at least in part, due to changes in the pattern of matrix degradation.

  • relaxin
  • hepatic stellate cell
  • hepatic fibrosis
  • type I collagen

  • Abbreviations used in this paper

    HSC
    hepatic stellate cells
    TIMP
    tissue inhibitor of metalloproteinases
    MMP
    matrix metalloproteinase
    α-SMA
    alpha smooth muscle actin
    TGF-β1
    transforming growth factor β1
    DMEM
    Dulbecco's minimal essential medium
    PBS
    phosphate buffered saline
    BSA
    bovine serum albumin
    TCA
    trichloracetic acid
    CCl4
    carbon tetrachloride

    • https://doi.org/10.1136/gut.49.4.577

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    • Abbreviations used in this paper

      HSC
      hepatic stellate cells
      TIMP
      tissue inhibitor of metalloproteinases
      MMP
      matrix metalloproteinase
      α-SMA
      alpha smooth muscle actin
      TGF-β1
      transforming growth factor β1
      DMEM
      Dulbecco's minimal essential medium
      PBS
      phosphate buffered saline
      BSA
      bovine serum albumin
      TCA
      trichloracetic acid
      CCl4
      carbon tetrachloride
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