PHOSPHOTIDYLCHOLINE SUPPRESSES PDGF INDUCED CELL ACTIVATION AND PROLIFERATION IN HEPATIC STELLATE CELLS: 46

Chronic Liver injury leading to cirrhosis is a costly disease with limited effective therapy. Liver fibrosis is characterized by excessive collagen matrix deposition. The hepatic stellate cell (HSC) is a major effector cell during fibrosis. Its activation in vivo and in vitro is associated with enhanced proliferation, collagen gene expression and matrix production. Effective therapy of hepatic fibrosis requires methodologies designed to prevent or modulate stellate cell activation. Polyunsaturated lecithin (phosphotidylcholine) has emerged as a promising new antifibrotic agent in the therapy of chronic liver disease. Lecithin is thought to prevent stellate cell deposition of collagen matrix through activation of collagenase activity. In addition, evidence has demonstrated that PPC prevented activation of stellate cells after an acetaldehyde challenge in vitro, suggesting that PPC might interfere with the activation of stellate cells. Furthermore, recent evidence has suggested that PPC might protect hepatocytes from lipid peroxidation by alcohol metabolites suggesting a potential antioxidant effect. Aim: The present study was desinged to determine whether PPC might have an acute effect on proliferation and the PDGF-induced signal transduction cascades of hepatic stellate cells. Methods: HSC were quiesced for 48 hours in 0.4% serum and MAPK activity was measured by immune complexed kinase assay. AP-1 activation was measured in nuclear lysates by gel shift assay. Proliferation was measured by 3H-thymidin incorporation. Results: We demonstrated that both PPC and dilineoylphosphatidyl choline (DLPC), the active component of PPC, decreased PDGF-induced activation of Mitogen activated protein kinase (MAPK) and decreased activation of the transcription factor AP-1 within minutes of exposure. Furthermore, we found stellate cells treated with DLPC had decreased PDGF-medical proliferation. Conclusion: These data show for the first time an inhibitory effect of phospholipids on in vitro HSC proliferation and on HSC activation cascade which acts within minutes of exposure. This suggests that there may be decreased proliferation/activation of stellate cells contributing to the antifibrogenic effects of PPC in vivo.