Differential effects of pyrrolidine dithiocarbamate on TNF-alpha-mediated liver injury in two different models of fulminant hepatitis.
OBJECTIVE
Pyrrolidine dithiocarbamate (PDTC) is an inhibitor of nuclear factor kappa B (NF-kappaB) activation. The present study aimed to investigate the effects of PDTC on lipopolysaccharide (LPS)-induced liver injury in two different models of fulminant hepatitis.


METHODS
Mice infected with Bacillus Calmette Guerin (BCG) were challenged with LPS (0.2 mg/kg) to induce the model of inflammatory liver injury. Mice were injected with D-galactosamine (GalN, 600 mg/kg) and LPS (20 microg/kg) to induce the model of apoptotic liver injury. In the treatment groups, mice were pre-treated with PDTC (100 mg/kg), initiated 24 h prior to LPS.


RESULTS
PDTC pretreatment reduced the infiltration of inflammatory cells, inhibited NF-kappaB activation and the expression of tumor necrosis factor alpha (TNF-alpha), attenuated nitric oxide production, and alleviated hepatic glutathione depletion. Correspondingly, PDTC reduced serum alanine aminotransferase, improved hepatic necrosis, and prolonged the survival in the BCG/LPS model. Conversely, PDTC accelerated death and aggravated liver apoptosis in the GalN/LPS model, although it reduced nitric oxide production, attenuated glutathione depletion, and inhibited the expression of TNF-alpha in liver.


CONCLUSIONS
PDTC protects mice against BCG/LPS-induced inflammatory liver injury through the repression of NF-kappaB-mediated TNF-alpha release, while it seems to be detrimental in GalN/LPS-induced apoptotic liver damage.
Lu
Jin-Wei
JW
Department of Toxicology, Anhui Medical University, Hefei, China.
Wang
Hua
H
Yan-Li
Ji
J
Zhang
Cheng
C
Ning
Huan
H
Li
Xiang-Yun
XY
Zhang
Heng
H
Duan
Zi-Hao
ZH
Zhao
Lei
L
Wei
Wei
W
Xu
De-Xiang
DX
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005688:Galactosamine / Q000009:adverse effects; D005978:Glutathione / Q000378:metabolism; D006505:Hepatitis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D017114:Liver Failure, Acute / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D009163:Mycobacterium bovis / Q000472:pathogenicity; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000975:Antioxidants; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C020972:pyrrolidine dithiocarbamic acid; D009569:Nitric Oxide; D005688:Galactosamine; D005978:Glutathione