Amelioration of liver injury by continuously targeted intervention against TNFRp55 in rats with acute-on-chronic liver failure.
PLoS One
; 8(7): e68757, 2013.
Article
em En
| MEDLINE
| ID: mdl-23874752
ABSTRACT
BACKGROUND:
Acute-on-chronic liver failure (ACLF) is an acute deterioration of established liver disease. Blocking the TNF (tumor necrosis factor)/TNFR (tumor necrosis factor receptor) 1 pathway may reduce hepatocyte apoptosis/necrosis, and subsequently decrease mortality during development of ACLF. We demonstrated that a long-acting TNF antagonist (soluble TNF receptor IgG Fc [sTNFRIgG-Fc]) prevented/reduced development of acute liver failure by blocking the TNF/TNFR1 (TNFRp55) pathway. However, it is still unclear if sTNFRIgG-Fc can inhibit hepatocyte damage during development of ACLF.METHODOLOGY:
Chronic liver disease (liver fibrosis/cirrhosis) was induced in Wistar rats by repeatedly challenging with human serum albumin (HSA), and confirmed by histopathology. ACLF was induced with D-galactosamine (D-GalN)/lipopolysaccharide (LPS) i.p. in the rats with chronic liver disease. Serum and liver were collected for biochemical, pathological and molecular biological examinations. PRINCIPALFINDINGS:
Reduced mortality was observed in sTNFRIgG-Fc treated ACLF rats, consistent with reduced interleukin (IL)-6 levels in serum and liver, as well as reduced hepatic caspase-3 activity, compared to that of mock treated group. Reduced hepatic damage was confirmed with histopathology in the sTNFRIgG-Fc treated group, which is consistent with reduced Bcl-2 and Bax, at mRNA and protein levels, but increased hepatocyte proliferation (PCNA). This is also supported by the findings that caspase-3 production was up-regulated significantly in ACLF group compared to the mock treated group. Moreover, up-regulated caspase-3 was inhibited following sTNFRIgG-Fc treatment. Finally, there was up-regulation of hepatic IL-22R in sTNFRIgG-Fc treated ACLF rats.CONCLUSIONS:
sTNFRIgG-Fc improved survival rate during development of ACLF via ameliorating liver injury with a potential therapeutic value.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Proteínas Recombinantes de Fusão
/
Falência Hepática Aguda
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Receptores Tipo I de Fatores de Necrose Tumoral
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Receptores Chamariz do Fator de Necrose Tumoral
Limite:
Animals
/
Humans
Idioma:
En
Revista:
PLoS One
Ano de publicação:
2013
Tipo de documento:
Article