title: Expression and role of myeloid-related protein-14 in clinical and experimental sepsis.
abstract: BACKGROUND
  Myeloid-related protein-8 (MRP8) and MRP14 can form heterodimers that elicit a variety of inflammatory responses. We showed that MRP8/14 is a ligand for Toll-like receptor-4, and that mice deficient in MRP8/14 are protected against endotoxic shock-induced lethality.
  
  
  OBJECTIVE
  To determine (1) the extent of MRP8/14 release in patients with sepsis and/or peritonitis and in healthy humans exposed to LPS and (2) the contribution of MRP8/14 to the host response in murine abdominal sepsis.
  
  
  METHODS
  MRP8/14 was measured in 51 patients with severe sepsis, 8 subjects after intravenous injection of LPS, and 17 patients with peritonitis. Host responses to sepsis were compared in mrp14 gene-deficient (and thereby MRP8/14-deficient) and wild-type mice intraperitoneally injected with Escherichia coli.
  
  
  RESULTS
  Patients with sepsis displayed elevated circulating MRP8/14 concentrations on both Days 0 and 3, and LPS injection resulted in systemic MRP8/14 release in healthy humans. In patients with peritonitis, MRP8/14 levels in abdominal fluid were more than 15-fold higher than in plasma. MRP14-deficient mice displayed improved defense against E. coli abdominal sepsis in an early phase, as indicated by diminished dissemination of the bacteria at 6 hours. In addition, MRP14-deficient mice demonstrated decreased systemic inflammation, as reflected by lower cytokine plasma concentrations, and less severe liver damage.
  
  
  CONCLUSIONS
  Human sepsis and endotoxemia are associated with enhanced release of MRP8/14. In abdominal sepsis, MRP8/14 likely occurs primarily at the site of the infection, facilitating bacterial dissemination at an early phase and liver injury.
authors.affiliation: Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. M.A.D.vanZoelen@umcutrecht.nl
authors.forename: Marieke A D
authors.initials: MA
authors.lastname: van Zoelen
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
authors.forename: Suzanne Q
authors.initials: SQ
authors.lastname: Van Veen
authors.forename: Jan W O
authors.initials: JW
authors.lastname: van Till
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tanck
authors.forename: Xavier
authors.initials: X
authors.lastname: Wittebole
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Laterre
authors.forename: Marja A
authors.initials: MA
authors.lastname: Boermeester
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000368:Aged; D000818:Animals; D040501:Calgranulin A / Q000235:genetics*; D040502:Calgranulin B / Q000235:genetics*; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000382:microbiology; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000150:complications* / Q000382:microbiology; D018805:Sepsis / Q000150:complications* / Q000235:genetics* / Q000382:microbiology
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B