Contribution of transforming growth factor-a to thr development of hepatic fibrosis in alcoholic liver diseases

虽然众所周知，酒精性肝病（ALD）发生肝纤维化而不伴有炎症，但其潜在机制尚不清楚。利用乙醇暴露的人HepG2肝母细胞瘤细胞作为ALD的模型，我们之前发现乙醇暴露导致HepG2细胞分泌一种多肽因子，刺激人IMR-90纤维母细胞瘤的胶原合成。本研究的目的是表征和确定这一因素。通过刺激IMR-90细胞中I型前胶原肽（PIC）合成的能力，评估了乙醇暴露的HepG2细胞在条件培养基（CM）中的胶原刺激活性。通过对各种细胞因子的抗体的能力来测试该因子的身份，以消耗CM的胶原刺激活性。采用酶联免疫吸附法测定乙醇处理HepG2细胞CM中转化生长因子(TGF)- α和ALD患者血清TGF- α水平。tgf - α抗体可使CM的胶原刺激活性降低。与此一致的是，乙醇处理HepG2的CM中tgf - α呈时间和剂量依赖性增加。ALD肝纤维化患者血清tgf - α水平明显高于慢性病毒性肝炎和病毒性肝硬化患者，提示tgf - α可能在ALD中发挥作用。总之，tgf - α可能参与ALD患者肝纤维化的发生。

Although it is well known that hepatic fibrosis develops in alcoholic liver diseases (ALD) without accompanying inflammation, the underlying mechanism is unclear. Using ethanol-exposed human HepG2 hepatoblastoma cells as a model for ALD, we previously found that ethanol exposure causes HepG2 cells to secrete a polypeptide factor which stimulates collagen synthesis in human IMR-90 fibroblasis. The aim of this study was to characterize and identify this factor.Collagen stimulating activity in conditioned media (CM) from ethanol-exposed HepG2 cells was assessed by its ability to stimulate synthesis of type I procollagen peptide (PIC) in IMR-90 cells. The identity of the factor was tested by the ability of antibodies to various cytokines to deplete collagen stimulating activity from CM.Transforming growth factor (TGF)-alpha in the CM of ethanol-treated HepG2 and serum TGF-alpha levels in patients with ALD were determined using an enzyme-linked immunosorbent assay. The collagen stimulating activity in CM could be depleted by antibody to TGF-alpha. Consistent with this, TGF-alpha in the CM of ethanol-treated HepG2 increased in a time-and dose-dependent manner. Suggesting that TGF-alpha may play a role in ALD, serum TGF-alpha levels in patients with ALD liver fibrosis were significantly higher than in patients with chronic viral hepatitis and viral cirrhosis. In conclusion, TGF-alpha may contribute to the development of hepatic fibrosis in ALD.