Pentoxifylline inhibits the proliferation and glycosaminoglycan synthesis of cultured fibroblasts derived from patients with Graves' ophthalmopathy and pretibial myxoedema

Abstract

Excessive amounts of glycosaminoglycans accumulate in the extraocular muscles of patients with Graves' ophthalmopathy and in the affected skin of patients with pretibial myxoedema. It is widely accepted that fibroblasts are the sources of glycosaminoglycan synthesis. Pentoxifylline, an analogue of the methylxanthine theobromine, inhibits the proliferation and certain biosynthetic activities of fibroblasts derived from normal human skin and from skin of patients with some fibrotic disorders. Our objective was to determine whether pentoxifylline has similar effects on fibroblasts derived from patients with Graves' ophthalmopathy and pretibial myxoedema and could serve as a candidate for the treatment of these manifestations. Fibroblasts from the extraocular muscles of two patients with Graves' ophthalmopathy and normal extraocular muscles of two subjects with strabismus, as well as the affected skin of two patients with pretibial myxoedema were cultured in vitro in the presence and absence of pentoxifylline to assay its effect on the proliferation of fibroblasts and their production of glycosaminoglycans. In subconfluent fibroblast cultures, pentoxifylline treatment caused a dose-dependent inhibition of serum-driven fibroblast proliferation. In confluent fibroblast cultures both in the presence and absence of serum, exposure to pentoxifylline similarly resulted in a dose-dependent inhibition of glycosaminoglycan synthesis for all these different kinds of fibroblasts. These findings may form the rationale for a clinical trial using pentoxifylline for the treatment of Graves' ophthalmopathy and pretibial myxoedema.

The effects of vitamin A, pentoxyfylline and methylprednisolone on experimentally induced amyloid arthropathy in brown layer chicks

“…It has also been reported that pentoxyfylline (Berman & Duncan, 1989;Aulthouse et al ., 1992;Chang et al ., 1993) and methylprednisolone (Laato et al ., 1989) have inhibitory effects on the synthesis of proteoglycans, glycosaminoglycans, collagen IV and fibronectin determined in amyloid (Skogen et al ., 1980;Lyon et al ., 1991;Gallo et al ., 1994;Ancsin & Kisilevsky, 1997;Landman et al ., 1998b).The role of pentoxyfylline and methylprednisolone in the prevention of amyloidosis should further be investigated.…”

“…A rise in intracellular cAMP has been suggested as a pentoxyfylline-mediated inhibitory effect on the respiratory burst of neutrophils (Besler et al ., 1986). Furthermore, pentoxyfylline has been shown to inhibit the synthesis of glycosaminoglycan, the production of fibronectin in cultured fibroblasts, the activity of collagenase and TNF-a (Berman & Duncan, 1989;Chang et al ., 1993).…”

Inhibition by pentoxifylline of extracellular signal‐regulated kinase activation by platelet‐derived growth factor in hepatic stellate cells

“…Concerning this latter effect, the bulk of the available experimental evidence is so far limited to sound studies performed on dermal fibroblasts (Berman et al, 1989;Chang et al, 1993;Duncan et al, 1995), in which, however, very little attention has been paid to an important aspect of fibrogenesis, namely Effect of PTF on intracellular cyclic AMP levels in human HSCs…”

“…In vitro studies, performed in cultured dermal fibroblasts, have suggested that PTF may exert an antifibrogenic effect by reducing the synthesis of extracellular matrix (ECM) components, including collagen type I and type III, by increasing collagenase activity, and by decreasing cell proliferation (Berman et al, 1989;Chang et al, 1993;Duncan et al, 1995).…”

Novel Approaches to the Management of Graves` Ophthalmopathy

“…This drug, an analogue of methylxanthine theobromine widely used for peripheral vascular disorders, has complex immunomodulatory effects on cytokine production 79 . Pentoxifylline inhibits proliferation and glycosaminoglycan synthesis of cultured orbital fibroblasts derived from GO patients 80 . In addition, this drug blocks glycosaminoglycan production and HLA-DR expression induced by IL-1, TNF-á and IFN-ã in orbital fibroblasts 81 .…”