title: Hepatic hepcidin protects against polymicrobial sepsis in mice by regulating host iron status.
abstract: BACKGROUND
  Hepcidin is a master regulator of iron metabolism primarily produced by the liver. Markedly increased hepcidin levels have been observed in septic individuals, while decreased hepatic hepcidin expression has been demonstrated in liver diseases that tend to develop into sepsis. However, the role of liver hepcidin in sepsis remains unknown.
  
  
  METHODS
  Mouse hepatic hepcidin expression was silenced using adenovirus-mediated hepcidin-specific short hairpin RNA injected via the tail vein. Sepsis was induced by cecal ligation and puncture, and the outcome (n = 23 for hepcidin knockdown mice, n = 15 for controls) and pathogenic changes (n = 5) related to sepsis were evaluated. The impact of alteration of iron status on the survival rate of hepatic hepcidin knockdown mice (n = 18 to 19) was also investigated.
  
  
  RESULTS
  Disruption of liver hepcidin expression increased serum iron level (537.8 ± 28.1 μg/dl [mean ± SD] vs. 235.9 ± 62.2 μg/dl; P < 0.05) and reduced iron content in the spleen macrophages at the steady state. Hepatic hepcidin knockdown mice not only showed increased 7-day mortality (73.9% vs. 46.7%; P < 0.05), but also had exacerbated organ damage and oxidative stress, as well as compromised host inflammatory responses and bacterial clearance at 24 h after polymicrobial sepsis. Treating the hepatic hepcidin knockdown mice with low-iron diet plus iron chelation decreased systemic iron content (serum level: 324.0 ± 67.4 μg/dl vs. 517.4 ± 13.4 μg/dl; P < 0.05) and rescued the mice from lethal sepsis (7-day survival: 36.8% vs. 83.3%; P < 0.01).
  
  
  CONCLUSIONS
  Hepatic hepcidin plays an important role in sepsis through regulation of iron metabolism. The findings may have potential therapeutic implications for liver diseases in which hepcidin expression is decreased.
authors.affiliation: From the Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: CongLi
authors.initials: C
authors.lastname: Zeng
authors.forename: QiXing
authors.initials: Q
authors.lastname: Chen
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.forename: QingHua
authors.initials: Q
authors.lastname: Chen
authors.forename: ShengWen
authors.initials: S
authors.lastname: Song
authors.forename: XiangMing
authors.initials: X
authors.lastname: Fang
mesh_terms: D000818:Animals; D015169:Colony Count, Microbial; D064451:Hepcidins / Q000235:genetics* / Q000502:physiology*; D007501:Iron / Q000097:blood / Q000378:metabolism*; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D009752:Nutritional Status / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D018805:Sepsis / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism
chemical_list: D064451:Hepcidins; D007501:Iron; D019255:NADPH Oxidases