Expression and role of myeloid-related protein-14 in clinical and experimental sepsis.
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.
van Zoelen
Marieke A D
MA
Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. M.A.D.vanZoelen@umcutrecht.nl
Vogl
Thomas
T
Foell
Dirk
D
Van Veen
Suzanne Q
SQ
van Till
Jan W O
JW
Florquin
Sandrine
S
Tanck
Michael W
MW
Wittebole
Xavier
X
Laterre
Pierre-François
PF
Boermeester
Marja A
MA
Roth
Johannes
J
van der Poll
Tom
T
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
D040501:Calgranulin A; D040502:Calgranulin B