Role of macrophage colony-stimulating factor in polymicrobial sepsis according to studies using osteopetrotic (op/op) mice.
BACKGROUND
The specific purpose of this study was to investigate the role of macrophage colony-stimulating factor (M-CSF)-induced macrophages in mouse polymicrobial sepsis model.


METHODS
M-CSF deficient (op/op) mice and their littermate mice w ere subjected the cecal ligation and puncture (CLP). Survival was assessed for the following 7 d after the CLP operation, and histopathologic findings were evaluated 12h after CLP. After CLP, expression of inflammatory mediators in serum was assessed by enzyme immunosorbent assay (ELISA). Furthermore, isolated peritoneal macrophages were stimulated with lipopolysaccharide (LPS) (10μg/mL) for 4h, and cytokine concentration in the supernatant was then measured by ELISA. Moreover, phagocytosis of isolated macrophages was assessed using fluorescent rates beads. In another set of experiments, effects of neutralization antibodies against high mobility group box 1 (HMGB1) were investigated in CLP model.


RESULTS
Mortality was increased in op/op mice compared with op/? mice after CLP. Furthermore, serum HMGB1 levels were also significantly greater in op/op mice than op/? mice. Production of HMGB1 by isolated peritoneal macrophages was significantly greater in op/op mice than op/? mice. Furthermore, the phagocytosis index was significantly blunted in op/op mice compared with op/? mice. Importantly, treatment with neutralization antibodies against HMGB1 markedly prevented acute lung injury and mortality in op/op mice.


CONCLUSIONS
Matured macrophages by M-CSF play pivotal role by scavenging endotoxin in inflammation. Furthermore, HMGB1 is involved in pathophysiology in polymicrobial sepsis, consistent with previous reports.
Ogiku
Masahito
M
First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
Kono
Hiroshi
H
Ishii
Kenichi
K
Hosomura
Naohiro
N
Fujii
Hideki
H
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004731:Endotoxins / Q000097:blood; D005260:Female; D024243:HMGB1 Protein / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides / Q000009:adverse effects; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000473:pathology* / Q000502:physiology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010022:Osteopetrosis / Q000473:pathology / Q000503:physiopathology*; D010587:Phagocytosis / Q000502:physiology; D018805:Sepsis / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D015996:Survival Rate
D000906:Antibodies; D016207:Cytokines; D004731:Endotoxins; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D016173:Macrophage Colony-Stimulating Factor