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.
Department of Physiology, School of Medicine, University of Málaga, Málaga, Spain.
Federico
F
Tutau
Carlos
C
Rodríguez-Ortigosa
Juan Enrique
JE
Puche
Nerea
N
Juanarena
Iñigo
I
Monreal
María
M
García Fernández
Encarna
E
Clavijo
Alberto
A
Castilla
Inma
I
Castilla-Cortázar
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