PENTOXIFYLLINE BLOCKS HEPATIC STELLATE CELL ACTIVATION INDEPENDENTLY OF PHOSPHODIESTERASE INHIBITORY ACTIVITY

Activated, but not quiescent, hepatic stellate cells (lipocytes) have a high level of collagen type I and smooth muscle actin (SMA) gene exp ression. Therefore, stellate cell activation is a critical step in hep atic fibrosis. The mechanisms leading to stellate cell activation in v ivo are unknown. The characteristic hepatic oxidative stress cascade i nduced in rats by CCl4 markedly stimulated stellate cell entry into S phase, nuclear factor (NF)-kappa B activity, and c-myb expression. The se changes were prevented by pentoxifylline, which also decreased CCl4 -induced hepatic injury. As expected, cAMP-mediated phosphorylation of CREB-Ser(133) was induced in vivo in stellate cells by pentoxifylline but not by its metabolite 5, an N-1 carboxypropyl derivative, which l acks phosphodiesterase inhibitory activity. Stellate cell nuclear extr acts from CCl4-treated, but not from control, animals formed a complex with the critical promoter E box of the alpha-SMA gene, which was dis rupted by c-myb antibodies and competed with by c-myb cognate DNA. Tre atment with pentoxifylline or metabolite 5 prevented the molecular abn ormalities characteristic of stellate cell activation induced by CCl4. These results suggest that induction of c-myb plays an important role in the in vivo activation of stellate cells. Pentoxifylline blocks st ellate cell activation in vivo independently of its inhibitory effects on phosphodiesterases by interfering with the oxidative stress cascad e and the activation of NF-kappa B and c-myb.