TRANSFORMING GROWTH FACTOR-BETA-1 AND FACTOR-ALPHA IN CHRONIC LIVER-DISEASE - EFFECTS OF INTERFERON ALFA THERAPY
TRANSFORMING GROWTH FACTOR-BETA-1 AND FACTOR-ALPHA IN CHRONIC LIVER-DISEASE - EFFECTS OF INTERFERON ALFA THERAPY
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DOI：
10.1056/nejm199104043241401
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发表时间：
1991-04-04
影响因子：
158.5
通讯作者：
FAUSTO, N
中科院分区：
文献类型：
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作者：
CASTILLA, A;PRIETO, J;FAUSTO, N
背景 肝硬化是一种弥漫性的肝纤维化过程，其病理机制尚不清楚。 转化生长因子（TGF）β-1诱导肝细胞产生细胞外基质蛋白，并与实验室动物肝纤维化的发病机制有关。 TGF-α是参与肝再生的肝细胞有丝分裂原。 应用北方印迹法对42例慢性肝炎、肝硬化和12例正常肝或脂肪肝患者肝组织中TGF-β 1 mRNA的表达进行了研究。 结果与肝组织中的I型前胶原mRNA、血清中的III型前胶原肽和组织学损伤程度的测量相关。 我们还研究了是否TGF-α mRNA将在肝活检标本中检测增殖活性。 TGF-β 1 mRNA表达与Ⅰ型前胶原mRNA表达（r = 0.94）、血清Ⅲ型前胶原肽（r = 0.89）及组织学活动指数（r = 0.73）密切相关。 所有纤维化活性增加的患者（血清III型前胶原肽水平> 11.9 μ g/L）的TGF-β-1 mRNA水平均增加（为对照组或正常纤维化活性患者水平的2 - 14倍），在再生结节患者中可检测到TGF-α和H3组蛋白（DNA合成的标志物）mRNA。 8例丙型肝炎患者中有6例接受α-干扰素治疗1年，临床反应持续，血清III型前胶原肽和转氨酶活性正常化。所有这些患者在年底获得的肝脏标本中TGF-β 1 mRNA水平均正常。 TGF-β 1可能在慢性肝病患者的纤维化发病机制中起重要作用，TGF-α表达可能与这些患者的肝再生有关。
Background. Cirrhosis is a diffuse process of hepatic fibrosis and regenerative nodule formation of unknown pathogenesis. Transforming growth factor (TGF) beta-1 induces the production of extracellular matrix proteins by liver cells and has been implicated in the pathogenesis of hepatic fibrosis in laboratory animals. TGF-alpha is a hepatocyte mitogen that participates in liver regeneration.Methods. Using Northern blot analysis, we studied the expression of TGF-beta-1 messenger RNA (mRNA) in liver specimens from 42 patients with chronic hepatitis and cirrhosis and 12 subjects with either normal or fatty livers. The results were correlated with measurements of procollagen Type I mRNA in liver tissue, procollagen Type III peptide in serum, and the degree of histologic injury. We also investigated whether TGF-alpha mRNA would be detectable in biopsy specimens of livers with proliferative activity.Results. TGF-beta-1 mRNA expression correlated closely with the expression of procollagen Type I mRNA (r = 0.94) and serum procollagen Type III peptide (r = 0.89) and with the histologic activity index (r = 0.73). All patients with increased fibrogenic activity (serum procollagen Type III peptide level, > 11.9-mu-g per liter) had increased levels of TGF-beta-1 mRNA (2 to 14 times the levels in the control group or in patients with normal fibrogenic activity), and both TGF-alpha and H3 histone (a marker of DNA synthesis) mRNAs were detectable in patients with regenerative nodules. Six of eight patients with hepatitis C treated with interferon alfa for one year had sustained clinical responses with normalization of serum procollagen Type III peptide and aminotransferase activity. All these patients had normal levels of TGF-beta-1 mRNA in liver specimens obtained at the end of the year.Conclusions. TGF-beta-1 may have an important role in the pathogenesis of fibrosis in patients with chronic liver disease, and TGF-alpha expression may be associated with liver regeneration in these patients.