Role of Acetaldehyde on PDGF-BB-induced HSC Migration and Proliferation.

描述(由申请人提供)：肝损伤伴随着肝星状细胞(HSC)向肌成纤维细胞的转分化(激活)，这是肝纤维化形成中的一个关键事件，导致增殖和迁移增加。这些通风口伴随着细胞-基质相互作用所需的细胞外基质成分的产生的变化，以及瘢痕组织的过量产生，包括I型胶原和纤维连接蛋白。因此，抑制HSC的转分化可以防止随后导致胶原过度沉积、纤维化和硬化的事件。HSC活化的一个特征是上调了血小板衍生生长因子-β受体(PDGF-Betar)，并增强了它们对PDGF-BB的迁移和增殖反应。虽然许多研究都集中在PDGF-BB依赖的分子事件导致细胞的增殖和迁移，但关于乙醇的第一代谢产物乙醛对PDGF-Betar表达和HSC增殖和迁移的作用知之甚少。此外，ACH和PDGF-BB在HSC基质相互作用中的作用还有待研究。基于我们以前的研究，即乙醛通过积累活性氧物种(过氧化氢)发挥部分作用，以及在这一应用中提出的初步结果，我们建议研究乙醛调节HSC中PDGF-Betar表达的分子机制。我们还将研究ACH在HSC对PDGF-BB的迁移和增殖反应中的作用，以及在细胞-基质相互作用中对PDGF-BB依赖的改变的作用。我们的长期目标是揭开乙醛引发的关键分子事件，这些事件可能导致治疗干预，从而预防和/或改善酒精性肝纤维化和肝硬变。

DESCRIPTION (provided by applicant): Liver injury is accompanied by trans-differentiation (activation) of hepatic stellate cells (HSC) into myofibroblasts, a key event in liver fibrogenesis that results in increased proliferation and migration. These vents are accompanied by alterations in the production of extracellular matrix components required for cell-matrix interactions and excess production of scar tissue, including type I collagen and fibronectin. Thus, inhibition of HSC trans-differentiation could prevent the subsequent events leading to excess collagen deposition, fibrosis and cirrhosis. A hallmark of HSC activation is the up-regulation of platelet-derived growth factor-beta receptor (PDGF-betaR) and their increased migratory and proliferative response to PDGF-BB. Although many studies have focused on PDGF-BB-dependent molecular events leading to cell proliferation and migration, little is known regarding the role of acetaldehyde, the first metabolite of ethanol, on PDGF-betaR expression and HSC proliferation and migration. Moreover, the role of ACH and PDGF-BB on HSC matrix interactions remains to be investigated. Based on our previous studies, namely that acetaldehyde exerts some of its action via the accumulation of reactive oxygen species (hydrogen peroxide) and the preliminary results presented in this application we propose to investigate molecular mechanisms whereby acetaldehyde modulates the expression of PDGF-betaR in HSC. We will also study the role of ACH on the migratory and proliferative responses of HSC to PDGF-BB and on the PDGF-BB-dependent alterations in cell-matrix interactions. Our long term goal is to unravel key molecular events triggered by acetaldehyde that could lead to therapeutic intervention and thus, to prevention and/or amelioration of alcohol-induced liver fibrosis and cirrhosis.