Enhanced actions of insulin-like growth factor-I and interferon-α co-administration in experimental cirrhosis


Inma Castilla de Cortázar Larrea, Department of Medical Physiology. School of Medicine, University USP-CEU, Campus Montepríncipe, 28660, Boadilla del Monte, Madrid, Spain
Tel: +34 686 652 710
Fax: +34 91 359 44 79
e-mails: iccortazar@uma.es, iccortazar@ceu.es


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-α (IFN-α) therapy seems to suppress the progression of hepatic fibrosis.

Aims: The aim of this study was to investigate the effect of the co-administration of IGF-I+IFN-α to Wistar rats with CCl4-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-β (TGF-β), α-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-α exerted significant effects on fibrogenesis. IGF-I significantly increased serum albumin and HGF whereas IFN-α-therapy did not. The inhibition of TGF-β expression was only observed by the effect of IFN-α-therapy. In addition, only the co-administration of IGF-I and IFN-α 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.

Conclusion: 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.