Pentoxifylline reduces in vitro renal myofibroblast proliferation and collagen secretion

Interstitial myofibroblasts (MF) are cells with features of both smooth mus cle cells and fibroblasts. They have been universally recognized in situati ons of tubulointerstitial injury, where their presence has been shown to be a marker of disease progression. The objective of this study was to determ ine if functions of MF relevant to fibrogenesis can be modified in vitro by the phosphodiesterase inhibitor pentoxifylline (PTX). MF were obtained Fro m sub-culture of normal rat kidney explant outgrowths maintained in DMEM 20% fetal calf serum (FCS), supplemented with antibiotics. Cells were chara cterized on the basis of growth characteristics and immunohistochemistry. M F constituted >95% of cells at passage 3. Cell culture media was supplement ed with the potential antagonist PTX alone (0, 1, 10, 100 mu g/ml) and in c ombination with TGF beta(1) (5 ng/ml). Population kinetics, proliferation a nd collagen production were determined from cell growth, [H-3]thymidine inc orporation and [3H]proline incorporation in collagenous proteins, respectiv ely. Both serum-stimulated population growth and proliferation were reduced in a linear fashion by 1, 10 and 100 mu g/ml PTX (all p < 0.05 versus 0 mu g/ml). Effect of PTX on cell population growth was however reversible when PTX was removed. Basal collagen secretion was decreased by PTX at 10 and 1 00 mu g/ml (p < 0.05 versus 0 mu g/ml), although cell layer collagen remain ed unchanged. Collagen production (secreted and cell layer) was augmented b y 5 ng/ml TGF beta(1). These effects on collagen production were partially reduced when 100 mu g/ml PTX was added. The authors conclude that myofibrob last function can be altered with agonists/antagonists. Attempts to down-re gulate fibrogenic functions of MF may therefore offer a valuable therapeuti c strategy. Copyright (C) 2000 S. Karger AG, Basel.