Expression of hyaluronic acid in N-nitrosodimethylamine induced hepatic fibrosis in rats

Int J Biochem Cell Biol. 2004 Feb;36(2):307-19. doi: 10.1016/s1357-2725(03)00253-x.


Hyaluronic acid (HA) plays prominent role in the pathogenesis of liver fibrosis. The mechanism of increased serum and liver HA during hepatic fibrosis was studied in rats. Liver injury was induced by intraperitoneal injections of N-nitrosodimethylamine (NDMA) for 7 consecutive days. A group of animals were sacrificed on everyday during injection and also on days 14 and 21 after the start of NDMA administration. The alpha-smooth muscle actin (alpha-SMA) was stained as a marker for activated stellate cells. Liver HA was studied by histochemical methods and serum HA was monitored by HA binding protein assay. CD44 was stained immunohistochemically. After the start of NDMA administration, necrosis was initiated on day 3 and massive necrosis was observed on days 5 and 7. Fibrosis was developed on day 14 and early cirrhosis was present on day 21. Staining of alpha-SMA demonstrated activated stellate cells from day 3 onwards. Serum HA peaked on day 7 and reduced afterwards. Serial liver sections stained for HA revealed excessive accumulation of HA during NDMA administration. On days 14 and 21, alpha-SMA and HA staining was remarkable in fibrotic and cirrhotic areas. CD44 staining was negative except during necrosis. It is concluded that the early elevation of serum HA is due to the increased synthesis and simultaneous release from the necrotic liver. In latter stages the increase of both serum and liver HA is contributed by the increased synthesis by the activated stellate cells and reduced clearance by the impaired sinusoidal endothelial cells.

MeSH terms

  • Actins / metabolism
  • Animals
  • Body Weight
  • Dimethylnitrosamine
  • Fibrosis / chemically induced
  • Fibrosis / pathology*
  • Hyaluronan Receptors / biosynthesis
  • Hyaluronic Acid / blood
  • Hyaluronic Acid / metabolism
  • Hyaluronic Acid / physiology*
  • Immunohistochemistry
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Muscle, Smooth / metabolism
  • N-Methylaspartate / pharmacology
  • Necrosis
  • Nitrosamines / chemistry*
  • Organ Size
  • Rats
  • Time Factors


  • Actins
  • Hyaluronan Receptors
  • Nitrosamines
  • N-Methylaspartate
  • Hyaluronic Acid
  • Dimethylnitrosamine