Enhanced actions of insulin-like growth factor-I and interferon-alpha co-administration in experimental cirrhosis.
BACKGROUND
Cirrhosis is a diffuse process of hepatic fibrosis and regenerative nodule formation. The liver is the major source of circulating insulin-like growth factor-I (IGF-I) whose plasma levels are diminished in cirrhosis. IGF-I supplementation has been shown to induce beneficial effects in cirrhosis, including antifibrogenic and hepatoprotective effects. On other hand, interferon-alpha (IFN-alpha) therapy seems to suppress the progression of hepatic fibrosis.


OBJECTIVE
The aim of this study was to investigate the effect of the co-administration of IGF-I+IFN-alpha to Wistar rats with CCl(4)-induced cirrhosis, exploring liver function tests, hepatic lipid peroxidation and histopathology.


METHODS
The mechanisms underlying the effects of these agents were studied by reverse transcription-polymerase chain reaction, determining the expression of some factors [hepatocyte growth factor (HGF), transforming growth factor-beta (TGF-beta), alpha-smooth muscle actin, collagen, tissular inhibitor of metalloproteinases-1 and pregnane X receptor (PXR)] involved in fibrogenesis, fibrolysis and/or hepatoprotection.


RESULTS
Both IGF-I and IFN-alpha exerted significant effects on fibrogenesis. IGF-I significantly increased serum albumin and HGF whereas IFN-alpha-therapy did not. The inhibition of TGF-beta expression was only observed by the effect of IFN-alpha-therapy. In addition, only the co-administration of IGF-I and IFN-alpha was able to increase the PXR. The combined therapy with both factors improved liver function tests, hepatic lipid peroxidation and reduced fibrosis, inducing a relevant histological improvement, reducing fibrosis and recovering hepatic architecture.


CONCLUSIONS
The co-administration IGF-I+IFN enhanced all the beneficial effects observed with each factor separately, showing an additive action on histopathology and PXR expression, which is involved in the inhibition of fibrogenesis.
Tutau
Federico
F
Department of Physiology, School of Medicine, University of Málaga, Málaga, Spain.
Rodríguez-Ortigosa
Carlos
C
Puche
Juan Enrique
JE
Juanarena
Nerea
N
Monreal
Iñigo
I
García Fernández
María
M
Clavijo
Encarna
E
Castilla
Alberto
A
Castilla-Cortázar
Inma
I
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D004359:Drug Therapy, Combination; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000494:pharmacology*; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D009841:Oligonucleotides / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012709:Serum Albumin / Q000378:metabolism; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016898:Interferon-alpha; D009841:Oligonucleotides; D012709:Serum Albumin; D016212:Transforming Growth Factor beta; D007334:Insulin-Like Growth Factor I; D002251:Carbon Tetrachloride