异羟肟酸苯丁酰苯胺：一种用于肺纤维化的潜在表观遗传治疗剂？
Suberoylanilide hydroxamic acid: a potential epigenetic therapeutic agent for lung fibrosis?
作者信息
Wang Z, Chen C, Finger S N, Kwajah S, Jung M, Schwarz H, Swanson N, Lareu F F, Raghunath M
机构信息
Tissue Modulation Laboratory, Division of Bioengineering, Faculty of Engineering, National University of Singapore, Singapore.
出版信息
Eur Respir J. 2009 Jul;34(1):145-55. doi: 10.1183/09031936.00084808.
Pulmonary fibrosis represents a fatal stage of interstitial lung diseases of known and idiopathic aetiology. No effective therapy is currently available. Based on an indication-discovery approach we present novel in vitro evidence that the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA), an FDA approved anti-cancer drug, has antifibrotic and anti-inflammatory potential. Human lung fibroblasts (fetal, adult and idiopathic adult pulmonary fibrosis) were treated with transforming growth factor (TGF)-beta 1 with or without SAHA. Collagen deposition, alpha-smooth muscle actin (alpha-SMA) expression, matrix metalloproteinase (MMP)1 activity, tissue inhibitor of MMP (TIMP)1 production, apoptosis and cell proliferation were assessed. Pro-inflammatory cytokines relevant to pulmonary fibrosis were assayed in SAHA-treated human peripheral blood mononuclear cells (PBMC) and its subpopulations. SAHA abrogated TGF-beta 1 effects on all the fibroblast lines by preventing their transdifferentiation into alpha-SMA positive myofibroblasts and increased collagen deposition without inducing apoptosis. However, MMP1 activity and TIMP1 production was modulated without a clear fibrolytic effect. SAHA also inhibited serum-induced proliferation of the fibroblast lines and caused hyperacetylation of alpha-tubulin and histone. Cytokine secretion was inhibited from PBMC and lymphocytes at nonapoptotic concentrations. Taken together, these data demonstrate combined antifibrotic and anti-inflammatory properties of SAHA, suggesting its therapeutic potential for pulmonary fibrosis.
肺纤维化代表了已知病因和特发性病因的间质性肺疾病的致命阶段。目前尚无有效的治疗方法。基于一种适应症发现方法，我们提供了新的体外证据，表明组蛋白去乙酰化酶抑制剂伏立诺他（SAHA），一种美国食品药品监督管理局（FDA）批准的抗癌药物，具有抗纤维化和抗炎潜力。用人转化生长因子（TGF）-β1处理人肺成纤维细胞（胎儿、成人和特发性成人肺纤维化患者的成纤维细胞），同时或不同时添加SAHA。评估胶原蛋白沉积、α-平滑肌肌动蛋白（α-SMA）表达、基质金属蛋白酶（MMP）1活性、MMP组织抑制剂（TIMP）1产生、细胞凋亡和细胞增殖。在SAHA处理的人外周血单核细胞（PBMC）及其亚群中检测与肺纤维化相关的促炎细胞因子。SAHA通过阻止成纤维细胞系转分化为α-SMA阳性肌成纤维细胞，消除了TGF-β1对所有成纤维细胞系的影响，并增加了胶原蛋白沉积，而不诱导细胞凋亡。然而，MMP1活性和TIMP1产生受到调节，但没有明显的纤溶作用。SAHA还抑制血清诱导的成纤维细胞系增殖，并导致α-微管蛋白和组蛋白的超乙酰化。在非凋亡浓度下，PBMC和淋巴细胞的细胞因子分泌受到抑制。综上所述，这些数据证明了SAHA具有抗纤维化和抗炎的综合特性，表明其对肺纤维化的治疗潜力。
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