Inhibition of hyaluronan synthesis by vesnarinone in cultured human myofibroblasts

Hyaluronan (HA), which is a major component of the extracellular matrix (EC M), is regulated during myofibroproliferative responses to numerous forms o f inflammatory stimuli. It is a key factor involved in cellular migration a nd adherence. The development of a potent and non-toxic inhibitor of HA syn thesis would open up a new avenue for the treatment of fibrocontractive dis eases such as pulmonary fibrosis and liver cirrhosis. In this study, the ef fects of vesnarinone (OPC-8212: 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-p iperazinyl]-2(1H)-quinolinone) on the secretion of HA in human myofibroblas t cell lines (MRC-5 and LI90 cells, referred to as pulmonary and hepatic my ofibroblasts, respectively) were examined. Vesnarinone specifically and dos e-dependently inhibited HA secretion by myofibroblasts up-regulated by feta l calf serum (FCS). The treatment of vesnarinone did not modify the phenoty pe of myofibroblast cells in culture. Vesnarinone also potently inhibited t he PIA secretion by the two myofibroblast cell lines up-regulated by transf orming growth factor-beta 1 (TGF-beta 1) or tumor necrosis factor-alpha (TN F-alpha). The addition of vesnarinone to myofibroblasts resulted in a signi ficant decrease of HA synthase (HAS) activity, with or without the addition of FCS or either cytokine. These findings suggest that vesnarinone inhibit s the secretion of HA in myofibroblasts by specifically suppressing HAS act ivity, and may therefore prove useful for the treatment of chronic inflamma tion and tissue fibrosis. (C) 2000 Elsevier Science B.V. All rights reserve d.