Potential conflict of interest: Nothing to report.
The mechanism behind the novel fibrosis recently described in NASH in HEPATOLOGY 2011 and Elsewhere†
Article first published online: 4 OCT 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 4, page 1585, October 2012
How to Cite
Hemsworth-Peterson, T. C. (2012), The mechanism behind the novel fibrosis recently described in NASH in HEPATOLOGY 2011 and Elsewhere. Hepatology, 56: 1585. doi: 10.1002/hep.25784
- Issue published online: 4 OCT 2012
- Article first published online: 4 OCT 2012
- Accepted manuscript online: 13 APR 2012 12:45PM EST
- Manuscript Accepted: 10 FEB 2012
To the Editor:
The recent flurry of exciting reports on the potential antifibrotic benefit of pentoxifylline (PTX) in nonalcoholic steatohepatitis (NASH)1, 2 has encouraged me to write this letter to the Editor of HEPATOLOGY to include some earlier reports in this area of hepatology research. We were the first to report that platelet-derived growth factor (PDGF) played a role in experimental hepatic fibrosis and describe its role in human fibrosis.3, 4 PTX blocked fibrosis via an effect on PDGF, by inhibiting phosphorylation of c-Jun on serine 73.5 Our results in NASH6, 7 and hepatitis C virus (HCV)8 showed that ribavirin, but not interferon, inhibited fibrosis, and that this effect was mediated by the block of phosphorylation of c-Jun on serine 73, resulting in decreased synthesis of collagen and decreased hepatic stellate cell proliferation. PTX decreased NASH sera-stimulated Fibrogenic Stimulation Index (FSI; our patented diagnostic test) and c-Jun phosphorylation as assessed by 3H-thymidine incorporation and Western analysis, respectively.9 Our recent data10 indicate that PTX decreased the FSI, and that the FSI correlates well with the METAVIR fibrosis score in HCV patients and may be predictive of fibrosis in this cohort.
- 1Pentoxifylline for steatohepatitis: magic bullet or smoking gun? HEPATOLOGY 2011; 54: 1496-1499., .
- 2HEPATOLOGY 2011; 54: 1610-1619., , , , , , et.al.
- 3Fibroproliferation in liver disease, role of monocyte factors. HEPATOLOGY 1992; 15: 191-197., .
- 4Pentoxifylline prevents fibrosis in an animal model and inhibits platelet derived growth factor driven proliferation of fibroblasts. HEPATOLOGY 1993; 17: 486-493..
- 5Selective down regulation of c-jun expression by pentoxifylline and c-jun antisense interrupts PDGF signalling: pentoxifylline inhibits phosphorylation of c-jun on serine 73. Mol Pharm 2002; 61: 1-13., , , , .
- 6The zonal distribution of megamitochondria with crystalline inclusions in early and advanced NASH. HEPATOLOGY 2004; 39: 1423-1429., , , , , , et al.
- 7Nonalcoholic fatty liver (NAFL): overview. In: Okita K, ed. NASH and Nutritional Therapy. New York, NY: Springer-Verlag; 2005: 1-43., , , , , , et al.
- 8Effect of fetuin, a TGFbeta antagonist and pentoxifylline, a cytokine antagonist on hepatic stellate cell function and fibrotic parameters in fibrosis. Eur J Pharmacol 2007; 572: 220-227., , .
- 9Effect of interferon, ribavirin, pentoxifylline and IL- 18 antibody on hepatitis C sera-stimulated hepatic stellate cell proliferation. J Interferon Cytokine Res 2008; 28: 5-14., , .
- 10Utility of the Fibrogenic Stimulation Index (FSI) in documenting fibrosis in NASH [Abstract]. Clin Exp Med J 2009; (Suppl): 3:574-575., , , .
Theresa C. Peterson M.D.*, * GI Division, Department of Medicine, Dalhousie University and QEII, Halifax, Canada.