Increased expression of toll-like receptor 4 enhances endotoxin-induced hepatic failure in partially hepatectomized mice.
OBJECTIVE
Liver failure associated with infections after hepatectomy remains a cause of mortality. It has recently been reported that toll-like receptor 4 (TLR4) is involved in recognizing lipopolysaccharides (LPS). The aim of this study was to investigate the role of TLR4 in endotoxin-induced liver injury after hepatectomy.


METHODS
C3H/HeN and C3H/HeJ mice underwent 70% hepatectomy or sham surgery, and LPS was administered 48 h after surgery. Expression of TLR4 mRNA, nuclear factor-kappaB (NF-kappaB) activation, tumor necrosis factor-alpha (TNF-alpha) and serum ALT levels, histological findings, and myeloperoxidase content were examined. Survival after LPS administration was also determined.


RESULTS
Hepatic expression of TLR4 was significantly increased 6-72 h after hepatectomy. In mice with endotoxemia after hepatectomy, hepatic NF-kappaB activation was greatly increased. Hepatic mRNA and serum levels of TNF-alpha, and ALT levels were significantly elevated compared with sham operated controls. Focal necrosis with neutrophil infiltration was apparent, which is consistent with increased myeloperoxidase contents in endotoxemia after hepatectomy in C3H/HeN mice. These were completely absent in C3H/HeJ mice. Survival of C3H/HeN mice with endotoxemia after hepatectomy was significantly lower than that of C3H/HeJ mice.


CONCLUSIONS
Upregulated TLR4 expression and function after hepatectomy plays a pivotal role in endotoxin-induced liver injury after hepatectomy.
Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo-ku, Chiba, 260-0856 Japan.
Tsukasa
T
Takayashiki
Hiroyuki
H
Yoshidome
Fumio
F
Kimura
Masayuki
M
Ohtsuka
Yoshiaki
Y
Shimizu
Atsushi
A
Kato
Hiroshi
H
Ito
Hiroaki
H
Shimizu
Satoshi
S
Ambiru
Akira
A
Togawa
Masaru
M
Miyazaki
D000818:Animals; D054426:Chemokine CXCL2; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D019446:Endotoxemia / Q000097:blood / Q000378:metabolism / Q000473:pathology; D004731:Endotoxins; D006498:Hepatectomy / Q000379:methods; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism / Q000473:pathology; D017093:Liver Failure / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D004731:Endotoxins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase