Curcumin improves sclerosing cholangitis in Mdr2-/- mice by inhibition of cholangiocyte inflammatory response and portal myofibroblast proliferation

Gut.  2010;59(4):521-30

 

Chronic cholangiopathies, such as primary sclerosing cholangitis (PSC) and primary biliary cirrhosis are characterised by progressive inflammation and subsequent development of biliary fibrosis and cirrhosis. Novel and effective medical treatment strategies are needed, as currently available treatment options are of little help in restricting or slowing the progression of cholangiopathies. It has been thought that cholangiocytes may contribute to propagation and progression of liver diseases by undergoing phenotypic and functional modifications, characterised by production of pro-inflammatory and profibrogenic mediators.

Curcumin has been shown to have anti-inflammatory, antioxidative and antifibrotic properties. Moreover, in hepatocytes, Curcumin was shown to inhibit inflammation-mediated alterations of hepatobiliary transporter gene expression, as a resultant of c-Jun N-terminal kinase (JNK) signalling blockade.

 

Objective:

To explore potential molecular mechanisms of Curcumin in multidrug-resistant protein 2 knockout (Mdr2-/-) mice, a genetic model of progressive cholangiopathy with biliary fibrosis.

 

Study Design:

  • Mdr2-/- mice (4 weeks old) were fed with either control diet or Curcumin-enriched (4% w/w) diet for 4 and 8 weeks
  • Correspondingly, Wild type (WT) mice of the same age received a control diet
  • During the first week, food intake was monitored on day 1, 3 and 7, and further monitored once a week, whereas gain in body weight (BW) was monitored daily
  • Liver weight (LW) was compared to the BW and the percentage ratio was calculated (LW/BW)
  • Various parameters like evaluation of enzyme activity, liver histology, immunohistochemistry, hepatic hydroxyproline (HP) content, liver protein concentration, measurement of bile flow and composition and cholangiocyte culture experiments were performed

 

Results and Discussion:

  • Curcumin-fed 8-week old Mdr2-/- mice group showed increased LW/BW ratio compared with age-matched WT mice
  • Four weeks of feeding with Curcumin resulted in reduced sclerosing cholangitis, ductular proliferation, serum liver enzymes (alanine aminotransferase and alkaline phosphatase) and bile acid levels in Mdr2-/- mice
  • Hepatic HP levels showed that after 4 weeks of Curcumin feeding, biliary fibrosis was reduced in Mdr2-/- mice
  • Furthermore, prolonged Curcumin feeding resulted in a more pronounced relative reduction of HP levels (42.7% after 8-week-feeding vs 21.9% reduction after 4-week-feeding)
  • Curcumin increased bile flow and biliary glutathione output in Mdr2-/- mice
  • Additionally, Curcumin reduced bile duct damage by inhibiting cholangiocyte activation via PPAR-gamma signalling

 

Conclusion:

Curcumin proved to be effective against cholangiopathy and biliary fibrosis that may have multiple targets in liver and thereby modulating several central cellular events in a mouse model of cholangiopathy.

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