title: Silencing airway epithelial cell-derived hepcidin exacerbates sepsis induced acute lung injury.
abstract: BACKGROUND
  The production of antimicrobial peptides by airway epithelial cells is an important component of the innate immune response to pulmonary infection and inflammation. Hepcidin is a β-defensin-like antimicrobial peptide and acts as a principal iron regulatory hormone. Hepcidin is mostly produced by hepatocytes, but is also expressed by other cells, such as airway epithelial cells. However, nothing is known about its function in lung infectious and inflammatory diseases. We therefore sought to investigate the role of airway epithelial cell-derived hepcidin in sepsis-induced acute lung injury.
  
  
  METHODS
  Acute lung injury was induced by polymicrobial sepsis via cecal ligation and puncture (CLP) surgery. Adenovirus-mediated short hairpin RNA specific for the mouse hepcidin gene hepc1 and control adenovirus were intratracheally injected into mice. The adenovirus-mediated knockdown of hepcidin in airway epithelial cells was evaluated in vivo. Lung injury and the 7-day survival rate were assessed. The levels of hepcidin-related iron export protein ferroportin were measured, and the iron content and function of alveolar macrophages were evaluated.
  
  
  RESULTS
  The hepcidin level in airway epithelial cells was upregulated during polymicrobial sepsis. The knockdown of airway epithelial cell-derived hepcidin aggravated the polymicrobial sepsis-induced lung injury and pulmonary bacterial infection and increased the mortality (53.33% in Ad-shHepc1 treated mice versus 12.5% in Ad-shNeg treated mice, P <0.05). The knockdown of hepcidin in airway epithelial cells also led to reduced ferroportin degradation and a low intracellular iron content in alveolar macrophages. Moreover, alveolar macrophages form the airway epithelial cell-derived hepcidin knockdown mice showed impaired phagocytic ability than those from the control mice.
  
  
  CONCLUSIONS
  Airway epithelial cell-derived hepcidin plays an important role in CLP induced acute lung injury. The severe lung injury in the airway epithelial cell-derived hepcidin knockdown mice is at least partially related to the altered intracellular iron level and function of alveolar macrophages.
authors.forename: Qi Xing
authors.initials: QX
authors.lastname: Chen
authors.forename: Sheng Wen
authors.initials: SW
authors.lastname: Song
authors.forename: Qing Hua
authors.initials: QH
authors.lastname: Chen
authors.forename: Cong Li
authors.initials: CL
authors.lastname: Zeng
authors.forename: Xia
authors.initials: X
authors.lastname: Zheng
authors.forename: Jun Lu
authors.initials: JL
authors.lastname: Wang
authors.forename: Xiang Ming
authors.initials: XM
authors.lastname: Fang
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000382:microbiology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000382:microbiology*; D060085:Coinfection; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000276:immunology / Q000502:physiology; D064451:Hepcidins / Q000276:immunology / Q000502:physiology*; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012137:Respiratory System; D018805:Sepsis / Q000150:complications / Q000382:microbiology*; D015996:Survival Rate
chemical_list: D064451:Hepcidins; D007501:Iron
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