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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.

References

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  • 1
    Sterling RK, Sanyal AJ. Pentoxifylline for steatohepatitis: magic bullet or smoking gun? HEPATOLOGY 2011; 54: 1496-1499.
  • 2
    Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, et.al. HEPATOLOGY 2011; 54: 1610-1619.
  • 3
    Peterson TC, Isbrucker RA. Fibroproliferation in liver disease, role of monocyte factors. HEPATOLOGY 1992; 15: 191-197.
  • 4
    Peterson TC. Pentoxifylline prevents fibrosis in an animal model and inhibits platelet derived growth factor driven proliferation of fibroblasts. HEPATOLOGY 1993; 17: 486-493.
  • 5
    Peterson TC, Peterson MR, Robertson HA, During M, Dragunow, M. Selective 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.
  • 6
    Le TH, Caldwell SH, Redick JA, Sheppard BL, Davis CA, Arseneau KO, et al. The zonal distribution of megamitochondria with crystalline inclusions in early and advanced NASH. HEPATOLOGY 2004; 39: 1423-1429.
  • 7
    Caldwell SH, Osaim A, Chang C, Davis C, Hespenheide E, Krugner-Higby L, et al. Nonalcoholic fatty liver (NAFL): overview. In: Okita K, ed. NASH and Nutritional Therapy. New York, NY: Springer-Verlag; 2005: 1-43.
  • 8
    Verma-Gandu M, Peterson MR, Peterson TC. Effect 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.
  • 9
    Khan F, Peltekian KM, Peterson TC. Effect 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.
  • 10
    Peterson TC, Khan F, Caldwell S, Peltekian KW. Utility 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.