Anti-high-mobility group box chromosomal protein 1 antibodies improve survival of rats with sepsis.
BACKGROUND
High-mobility group box chromosomal protein 1 (HMGB1) has recently been shown to be an important late mediator of endotoxin shock, intraabdominal sepsis, and acute lung injury, and a promising therapeutic target of severe sepsis. We sought to investigate the effect of antibodies to HMGB1 on severe sepsis in a rat cecal ligation and puncture (CLP) model.


METHODS
Adult male Sprague-Dawley rats underwent CLP and then were randomly divided into two groups: treatment with anti-HMGB1 polyclonal antibodies, and non-immune IgG-treated controls. The serum HMGB1 concentrations were measured at ten time points (preoperatively, and postoperatively at 4, 8, 20, 32, and 48 h and at 3, 4, 5, and 6 days). Hematoxylin-eosin staining, elastica-Masson staining, and immunohistochemical staining for HMGB1 were performed on the cecum and the lung to assess pathological changes 24 h after the CLP procedure.


RESULTS
Treatment with anti-HMGB1 antibodies significantly increased survival [55% (anti-HMGB1) vs. 9% (controls); P< 0.01]. The serum HMGB1 concentrations at postoperative hours 20 and 32 of the anti-HMGB1 antibody-treated animals were significantly lower than those of the controls (P < 0.05). Treatment with anti-HMGB1 antibodies markedly diminished the pathological changes and the number of HMGB1-positive cells in the cecum and the lung.


CONCLUSIONS
The present study demonstrates that anti-HMGB1 antibodies are effective in the treatment of severe sepsis in a rat model, thereby supporting the relevance of HMGB1 eradication therapy for severe sepsis.
Suda
Koichi
K
Department of Surgery, School of Medicine, Keio University, Shinanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan.
Kitagawa
Yuko
Y
Ozawa
Soji
S
Saikawa
Yoshiro
Y
Ueda
Masakazu
M
Ebina
Masahito
M
Yamada
Shingo
S
Hashimoto
Satoru
S
Fukata
Shinji
S
Abraham
Edward
E
Maruyama
Ikuro
I
Kitajima
Masaki
M
Ishizaka
Akitoshi
A
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D002432:Cecum / Q000473:pathology / Q000601:surgery; D004195:Disease Models, Animal; D024243:HMGB1 Protein; D006609:High Mobility Group Proteins / Q000097:blood / Q000276:immunology*; D007150:Immunohistochemistry; D008026:Ligation; D008297:Male; D009500:Neutralization Tests; D010538:Peritonitis / Q000276:immunology* / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000097:blood / Q000276:immunology*; D018805:Sepsis / Q000628:therapy*
D000906:Antibodies; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D006609:High Mobility Group Proteins; D012097:Repressor Proteins