title: Inhibition of the CXCL12/CXCR4 chemokine axis with AMD3100, a CXCR4 small molecule inhibitor, worsens murine hepatic injury.
abstract: OBJECTIVE
  Activation of hepatic stellate cells and development of chronic inflammation are two key features in the progression of hepatic fibrosis. We have shown that in vitro activated stellate cells increase their expression of CXCL12 as well as the receptor CXCR4 and that receptor engagement promotes a profibrogenic phenotype. Furthermore, injury promotes increased hepatic expression of CXCL12 and a massive infiltration of CXCR4-expressing leukocytes, granulocytes and myeloid cells. The primary site of inflammatory cell accumulation is around the CXCL12-rich portal tracts and within fibrotic septae, indicating a role for CXCR4 during injury. In order to characterize the relevance of the CXCR4/CXCL12 chemokine axis during hepatic injury we inhibited the axis using AMD3100, a CXCR4 small molecule inhibitor, in models of chronic and acute liver injury.
  
  
  METHODS
  Mice were subjected to acute and chronic CCl4 liver injury with and without AMD3100 administration. The degree of liver injury, fibrosis and the composition of the intrahepatic inflammatory response were characterized.
  
  
  RESULTS
  Treatment of mice with AMD3100 in the chronic CCl4 model of liver injury led to an increase in hepatic inflammation and fibrosis with a specific increase in intrahepatic neutrophils. Furthermore, in an acute model of CCl4 -induced liver injury, AMD3100 led to an increase in the number of intrahepatic neutrophils and a trend towards worse necrosis.
  
  
  CONCLUSIONS
  Together, this data suggests that inhibition of the CXCR4/CXCL12 chemokine axis is injurious through modulation of the hepatic inflammatory response and that this axis may serve a protective role in liver injury.
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Yedidya
authors.initials: Y
authors.lastname: Saiman
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: JingJing
authors.initials: J
authors.lastname: Jiao
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Fiel
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Costica
authors.initials: C
authors.lastname: Aloman
authors.affiliation: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Meena B
authors.initials: MB
authors.lastname: Bansal
keywords: CXCL12; CXCR4; hepatic stellate cells; liver fibrosis