[Caspase-12 expression and activation in the pathogenesis of acute hepatic failure induced by lipopolysaccharide and D-galactosamine].
OBJECTIVE
To study the role of caspase-12 expression on hepatocyte apoptosis in an experimental model of acute hepatic failure (AHF).


METHODS
A mouse experimental model of AHF was developed by intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-Gal). Hepatocyte apoptosis was examined by DNA agarose gel and liver pathology. Caspase-12 mRNA expression in liver was detected by reverse transcriptase PCR (RT-PCR) method. The expression of caspase-12, GRP78 proteins in livers was determined by Western blot.


RESULTS
Caspase-12 mRNA expression in the livers increased significantly from 5 to 7 hours after administration of LPS and D-Gal. Typical manifestation of hepatocyte apoptosis appeared at 5 hours after the drug administration. After 5 hours the level of serum ALT and AST were remarkably increased, and they reached the peak at 7 hours. The expression of procaspase-12 protein decreased obviously at 7 hours. Seven hours after the drug administration, hepatocyte apoptosis and necrosis both started. The marker of endoplasmic reticulum (ER) stress, Bip/GRP78 was activated during the development of hepatocyte apoptosis. The level of Bip/GRP78 protein was gradually increased at 5 hours after the drug induction.


CONCLUSIONS
Hepatocyte apoptosis plays an important role in the pathogenesis of AHF. Caspase-12 induced ER stress involves in hepatocyte apoptosis. It suggests that inhibition of caspase-12 activation might be a potential strategy in the treatment of AHF in the future.
Zhou
Hui-juan
HJ
Department of Infectious Diseases, Ruijin Hospital of Shanghai Second Medical University, Shanghai 200025, China.
Xie
Qing
Q
Jiang
Shan
S
Li
Guang-ming
GM
Zhou
Xia-qiu
XQ
Liu
Hai-fang
HF
Yu
Hong
H
Guo
Qing
Q
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053454:Caspase 12 / Q000096:biosynthesis* / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D005688:Galactosamine; D022781:Hepatocytes / Q000473:pathology; D008070:Lipopolysaccharides; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011897:Random Allocation
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D005688:Galactosamine; D053454:Caspase 12