title: Inhibition of Kupffer cells reduced CXC chemokine production and liver injury.
abstract: BACKGROUND
  Cytokine production is a critical component of ischemia/reperfusion (IR) injury. In the liver, Kupffer cells produce cytokines and chemokines (i.e., cytokines with chemoattractant properties) that are important mediators in neutrophil recruitment and subsequent hepatocellular injury. Therefore, the role of Kupffer cells in chemokine production in hepatic IR injury was investigated.
  
  
  METHODS
  Adult male C57BL/6 mice underwent 90 min of partial hepatic ischemia followed by various reperfusion times (i.e., 0, 1.5, 3, and 6 h). Gadolinium chloride (GC), which inhibits Kupffer cell activity, was administered to mice 48 and 24 h prior to ischemia. The control group received a corresponding volume of normal saline. Plasma levels of the cytokine macrophage inflammatory protein-2 (MIP-2), KC, and tumor necrosis factor (TNF)-alpha and liver mRNA were measured. Liver injury was assessed by plasma level of alanine transaminase (ALT) and histopathology.
  
  
  RESULTS
  A reperfusion time-dependent liver injury occurred as indicated by increased levels of plasma ALT and histopathology. The injury was associated with increased plasma TNF-alpha, MIP-2, and KC and their hepatic mRNA expression and neutrophil infiltration into ischemic lobes of the liver. GC treatment significantly reduced the number of Kupffer cells as determined by the immunostained liver tissue sections. The extent of liver injury significantly decreased in GC-treated mice that were associated with decreased levels of plasma ALT, TNF-alpha, MIP-2, and KC and neutrophil infiltration.
  
  
  CONCLUSIONS
  This study suggests that Kupffer cells are major contributors to cytokine production in hepatic IR and their modulation may serve as a potential target for therapeutic intervention.
authors.affiliation: Department of Surgery, College of Human Medicine, Michigan State University, East Lansing, MI 48824-1315, USA.
authors.forename: B
authors.initials: B
authors.lastname: Mosher
authors.forename: R
authors.initials: R
authors.lastname: Dean
authors.forename: J
authors.initials: J
authors.lastname: Harkema
authors.forename: D
authors.initials: D
authors.lastname: Remick
authors.forename: J
authors.initials: J
authors.lastname: Palma
authors.forename: E
authors.initials: E
authors.lastname: Crockett
mesh_terms: D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000097:blood / Q000235:genetics*; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000097:blood / Q000235:genetics*; D005682:Gadolinium / Q000494:pharmacology; D015870:Gene Expression / Q000276:immunology; D006133:Growth Substances / Q000097:blood / Q000235:genetics*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008107:Liver Diseases / Q000097:blood / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D009195:Peroxidase / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D015427:Reperfusion Injury / Q000097:blood / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005682:Gadolinium; D009195:Peroxidase; D000410:Alanine Transaminase; C038958:gadolinium chloride