title: Hepatic macrophages promote the neutrophil-dependent resolution of fibrosis in repairing cholestatic rat livers.
abstract: BACKGROUND
  Cholestatic liver injury from extrahepatic biliary obstruction is well characterized by inflammatory and fibrogenic mechanisms. Little is known, however, about mechanisms required to reverse injury and effect liver repair. We sought to determine the cellular and molecular requirements for repair after biliary decompression, focusing on the role of hepatic macrophages in regulating inflammation and matrix resolution.
  
  
  METHODS
  Male Sprague-Dawley rats underwent bile duct obstruction for 7 days followed by ductular decompression. Rats were treated with gadolinium chloride (GdCl(3)) to deplete the macrophage populations 24 or 48 hours before decompression. Liver tissue obtained at the time of decompression or after 2 days of repair was processed for morphometric analysis, immunohistochemistry, quantitative RT-PCR and in situ hybridization.
  
  
  RESULTS
  GdCl(3) treatment for either 24 or 48 hours before decompression reduced the numbers of ED2(+) Kupffer cells and ED1(+) inflammatory macrophages in obstructed livers; only 48 hours of pretreatment, however, reduced the neutrophil counts. Furthermore, 48-hour GdCl(3) pretreatment blocked matrix degradation. Quantitative polymerase chain reaction demonstrated decreased cytokine-induced neutrophil chemoattractant-1 (CINC-1; CXCL1) and intercellular adhesion molecule-1 mRNA expression after GdCl(3) treatment and the elimination of hepatic macrophages. Immunohistochemistry and in situ hybridization revealed that neutrophils and CINC-1 mRNA localize within regions of fibrotic activity during both injury and repair.
  
  
  CONCLUSIONS
  We conclude that the macrophage population is not directly involved in fibrotic liver repair. Rather, hepatic macrophages regulate the influx of neutrophils, which may play a direct role in matrix degradation.
authors.affiliation: Department of Surgery, The Warren Alpert Medical School of Brown University and Hasbro Children's Hospitals, Providence, RI 02903, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Harty
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Papa
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Huddleston
authors.forename: Ezekiel
authors.initials: E
authors.lastname: Young
authors.forename: Samantha
authors.initials: S
authors.lastname: Nazareth
authors.forename: Charles A
authors.initials: CA
authors.lastname: Riley
authors.forename: Grant A
authors.initials: GA
authors.lastname: Ramm
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gregory
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tracy
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1 / Q000378:metabolism; D001651:Cholestasis, Extrahepatic / Q000150:complications / Q000276:immunology*; D015870:Gene Expression; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D008115:Liver Regeneration / Q000276:immunology* / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat