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首页> 外文期刊>Cell discovery. >TAK1 inhibition attenuates both inflammation and fibrosis in experimental pneumoconiosis
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TAK1 inhibition attenuates both inflammation and fibrosis in experimental pneumoconiosis

机译：TAK1抑制可减轻实验性尘肺病的炎症和纤维化

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Pneumoconiosis, caused by inhalation of mineral dusts, is a major occupational disease worldwide. Currently, there are no effective drugs owing to a lack of potential therapeutic targets during either the inflammation or fibrosis molecular events in pneumoconiosis. Here, we performed microarrays to identify aberrantly expressed genes in the above molecular events in vitro and found a hub gene transforming growth factor-β-activated kinase 1 ( TAK1 ), which was highly expressed and activated in pneumoconiosis patients as well as silica-exposed rats with experimental pneumoconiosis. Genetic modulation of TAK1 by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9, RNA interference and overexpression indicated the important role of TAK1 in both inflammation and fibrosis in experimental pneumoconiosis. To achieve pharmacological TAK1 inhibition, we virtually screened out a natural product resveratrol, which targeted TAK1 at both N161 and A107 residues, and significantly inhibited TAK1 activation to attenuate inflammation and fibrosis in vitro . Consistently, in vivo prevention and intervention studies showed that resveratrol could inhibit pulmonary inflammation and fibrosis in silica-exposed rats.
机译：吸入矿物质粉尘引起的尘肺病是世界范围内的主要职业病。当前，由于在尘肺中的炎症或纤维化分子事件期间缺乏潜在的治疗靶标，因此没有有效的药物。在这里，我们进行了微阵列鉴定，以在上述分子事件中体外鉴定出异常表达的基因，并发现了一个轮毂基因转化生长因子-β-活化的激酶1（TAK1），该基因在尘肺病患者中以及在暴露于二氧化硅的环境中均得到了高表达和活化。实验性尘肺的大鼠。 CRISPR（聚集的规则间隔的短回文重复序列）/ Cas9对TAK1的遗传调节，RNA干扰和过表达表明TAK1在实验性尘肺病的炎症和纤维化中都起着重要作用。为了达到TAK1的药理抑制作用，我们实际上筛选出了天然产物白藜芦醇，其将TAK1靶向N161和A107残基，并显着抑制了TAK1的活化，从而减轻了体外的炎症和纤维化。一致地，体内预防和干预研究表明，白藜芦醇可以抑制接触二氧化硅的大鼠的肺部炎症和纤维化。

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