Mycophenolate mofetil prevents lethal acute liver failure in mice induced by bacille Calmette-Guérin and lipopolysaccharide.
OBJECTIVE
To investigate the effect of mycophenolate mofetil (MMF) on acute liver injury induced by bacille Calmette-Guérin (BCG) and lipopolysaccharide (LPS).


METHODS
Acute liver failure was induced in male Kunming strain mice by injecting the animals with BCG 2.5 mg per mouse, and LPS 10 microg per mouse 10 days later. The mice in the treatment groups were given MMF 2 h before, simultaneous with, or 2 h after administration of LPS, and the mice in the control group were given the same dose of saline. The 24-h survival rate, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were compared. Serum levels of tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and interleukin 6 (IL-6) were measured and the expressions of TNF-alpha, IFN-gamma, and IL-6 mRNA in the liver tissue were determined by reverse transcription-polymerase chain reaction (RT-PCR). Concanavalin A (Con A)-induced splenocyte proliferation were determined by methods of methyl thiazolyl tetrazolium.


RESULTS
Injecting a small dose of LPS into BCG-primed mice caused a lethal hepatic injury mimicking acute hepatitis, from which 16 of the 20 mice died within 24 h (20% survival rate). Massive necrosis of parenchymal hepatocytes with marked inflammatory cell infiltration was observed by histological examination. In parallel, serum ALT and TNF-alpha, IFN-gamma, and IL-6 levels were increased. Expression of TNF-alpha, IFN-gamma, and IL-6 mRNA in the liver were significantly increased also. Treatment with MMF markedly reduced the death rate in a dose-dependent manner. It reached its maximal effect at the dosage of 150 mg per kg of body weight when pretreated 2 h before LPS injection, with improvement of histological feather and survival rate (84.2%, 16/19). MMF significantly inhibited serum levels of TNF-alpha, IFN-gamma, and IL-6, and significantly reduced TNF-alpha, IFN-gamma, and IL-6 expression in the liver, which increased after BCG and LPS injection. Moreover, splenocyte proliferation response induced by Con A was also inhibited by MMF treatment.


CONCLUSIONS
Treatment with MMF has a protective effect on endotoxin-induced fatal liver failure by regulating the production of inflammatory cytokines and T-cell proliferation.
Yang
Yong-Feng
YF
Department of Liver Disease, Second Hospital of Nanjing, affiliated with the Medical School of South-East University, Nanjing, Jiangsu Province, China. henanyyf@hotmail.com
Tan
De-Ming
DM
Xie
Yu-Tao
YT
Zhao
Wei
W
Hou
Zhou-Hua
ZH
Zhong
Yan-Dan
YD
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001500:BCG Vaccine / Q000008:administration & dosage; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051379:Mice; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001500:BCG Vaccine; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D009173:Mycophenolic Acid