title: Kupffer cell inactivation delays repair in a rat model of reversible biliary obstruction.
abstract: BACKGROUND
  During cholestatic liver injury, Kupffer cells (KC) and activated macrophages modulate cell proliferation and subsequent matrix deposition. The role of KC in the restoration of cell architecture and matrix metabolism during repair following chronic cholestatic liver injury is unknown.
  
  
  METHODS
  To determine the effect of KC inactivation, adult male Sprague-Dawley rats underwent bile duct suspension (BDS) for 5 days followed by reversal of the obstruction. Saline (control) and gadolinium chloride (10 mg/kg) were administered 1 day prior to BDS and 1 day prior to reversal, to inactivate KC during both injury and repair. Serum bilirubin and quantitative cell morphometry were compared to verify the reversibility of the model. Collagen content of the liver was measured in trichrome-stained paraffin sections using NIH imaging software.
  
  
  RESULTS
  Reversibility of the obstruction was verified by normalization of direct serum bilirubin, which peaked at 8.42 +/- 0.76 mg/dL following 5 days of BDS and returned to sham-operated levels 2 days after reversal, 0.36 +/- 0.15 mg/dL. Hematoxylin and eosin (H&E)-stained paraffin-embedded liver sections from gadolinium-treated animals at 4 and 7 days after reversal exhibited persistent bile duct proliferation, matrix deposition, and inflammation. Gadolinium-treated animals had altered collagen metabolism compared to saline controls. Whereas the collagen content in the saline group slowly returned to sham-operated levels over time, the treatment group demonstrated progressive accumulation of collagen during repair which was statistically significant at 7 days following reversal (8.79%/mm(2) +/- 2.17 in gadolinium group vs 2. 33%/mm(2) +/- 0.34 in saline group, P = 0.0003).
  
  
  CONCLUSIONS
  These results demonstrate that inactivation of resident hepatic macrophages during liver repair impairs collagen metabolism, inhibits the resolution of fibrosis, and allows the persistence of inflammatory cell infiltrates in the portal areas. This is the first evidence of profibrogenic responses in the absence of an intact KC compartment during repair after cholestatic injury.
authors.affiliation: Rhode Island and Hasbro Children's Hospitals, Brown University School of Medicine, Providence, Rhode Island 02903, USA.
authors.forename: K K
authors.initials: KK
authors.lastname: Roggin
authors.forename: E F
authors.initials: EF
authors.lastname: Papa
authors.forename: A G
authors.initials: AG
authors.lastname: Kurkchubasche
authors.forename: T F
authors.initials: TF
authors.lastname: Tracy
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000473:pathology / Q000601:surgery; D001663:Bilirubin / Q000097:blood; D001835:Body Weight; D056486:Chemical and Drug Induced Liver Injury; D001651:Cholestasis, Extrahepatic / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D002908:Chronic Disease; D003094:Collagen / Q000032:analysis / Q000378:metabolism; D003287:Contrast Media; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005682:Gadolinium; D006965:Hyperplasia; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D008107:Liver Diseases / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003287:Contrast Media; D003094:Collagen; D005682:Gadolinium; C038958:gadolinium chloride; D001663:Bilirubin