Phenylbutyrate decreases type I collagen production in human lung fibroblasts
Phenylbutyrate decreases type I collagen production in human lung fibroblasts
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DOI：
10.1002/jcb.10742
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发表时间：
2004-03-01
影响因子：
4
通讯作者：
Goldstein, RH
中科院分区：
文献类型：
--
作者：
Rishikof, DC;Ricupero, DA;Goldstein, RH
纤维化性肺病的特点是细胞外基质，特别是I型胶原蛋白产生过多。苯丁酸酯（PB）是一种无毒的药理化合物，其功能是弱组蛋白去乙酰化酶抑制剂。在肝星状细胞中，I型胶原的合成表达通过抑制组蛋白乙酰化而降低。我们的研究考察了PB在人肺成纤维细胞中对I型胶原蛋白的调节。我们发现PB降低了基础和转化生长因子β刺激的α 1(I)胶原mRNA和蛋白水平。Northern blot分析表明，PB使α 1(I)胶原mRNA的稳态水平降低了78%，但没有显著改变mRNA转录物的稳定性。PB刺激cAMP的产生并增加组蛋白H4的乙酰化，但不影响两种转化生长因子- β (tgf - β)应答荧光素酶报告结构的活性。这些数据表明，PB通过cAMP产生和组蛋白乙酰化等机制调节人肺成纤维细胞中I型胶原的表达。PB可能对纤维化肺疾病有治疗作用。(C) 2004 Wiley-Liss, Inc。
Fibrotic lung diseases are characterized by excess extracellular matrix production, in particular type I collagen. Phenylbutyrate (PB) is a non-toxic pharmacological compound that functions as a weak histone deacetylase inhibitor. In hepatic stellate cells, the synthesis of type I collagen expression is decreased by inhibiting histone acetylation. Our studies examined the regulation of type I collagen by PB in human lung fibroblasts. We found that PB decreases basal and transforming growth factor-beta-stimulated alpha1(I) collagen mRNA and protein levels. Northern blot analyses demonstrated that PB decreases steady-state alpha1(I) collagen mRNA levels by 78% without significantly changing the stability of the mRNA transcript. PB stimulates cAMP production and increases the acetylation of histone H4, but does not affect the activity of two transforming growth factor-beta (TGF-beta)-responsive luciferase reporter constructs. These data suggest that PB regulates type I collagen expression in human lung fibroblasts by mechanisms that include cAMP production and histone acetylation. PB may have therapeutic use in fibrotic lung diseases.. (C) 2004 Wiley-Liss, Inc.