Histone deacetylase inhibitors suppress RSV infection and alleviate virus-induced airway inflammation.
Histone deacetylase inhibitors suppress RSV infection and alleviate virus-induced airway inflammation.
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组蛋白脱乙酰酶抑制剂抑制 RSV 感染并减轻病毒引起的气道炎症
DOI：
10.3892/ijmm.2016.2691
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发表时间：
2016-09
影响因子：
5.4
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Feng Q;Su Z;Song S;Χu H;Zhang B;Yi L;Tian M;Wang H
呼吸道合胞病毒（RSV）是婴幼儿下呼吸道感染的主要原因。然而，大多数RSV感染患者仅表现出轻微症状。RSV感染人群中不同的感染严重程度和反应表明，表观遗传调节以及个人遗传背景可能会影响RSV的感染性。组蛋白去乙酰化酶（HDAC）是肺部疾病中重要的表观遗传调节因子。本研究的目的是探讨HDAC表达与RSV诱导的肺部炎症之间的可能联系。为了解决这个问题，制备RSV感染的气道上皮细胞（BEAS-2B）并建立RSV感染的小鼠模型，然后用各种浓度的HDAC抑制剂（HDACis），即曲马斯他丁A（TSA）和辛二酰苯胺异羟肟酸（SAHA）处理。评估病毒复制和病毒诱导的气道炎症或氧化应激的标志物。Western blot分析核因子-κB（NF-κB）、环氧化酶-2（考克斯-2）、丝裂原活化蛋白激酶（MAPK）和信号转导和转录激活因子3（STAT 3）信号通路的激活情况。我们的研究结果表明，呼吸道合胞病毒感染的气道上皮细胞（AEC）显着降低组蛋白乙酰化水平，通过改变HDAC 2的表达。用HDAC治疗RSV感染的AEC通过上调干扰素-α（IFN-α）相关信号通路显著限制RSV复制。用HDACis治疗RSV感染的AEC还显著抑制了RSV诱导的促炎细胞因子释放[白细胞介素（IL）-6和IL-8]和氧化应激相关分子产生[丙二醛（MDA）和一氧化氮（NO）]。NF-κB、考克斯-2、MAPK和Stat 3的活化也被显著抑制，这些活化协调了促炎基因表达和氧化应激损伤。我们使用RSV感染小鼠模型的体内研究验证了这些结果。用HDAC治疗减轻气道炎症并减少体内RSV复制。我们的数据表明，RSV通过增强HDAC 2表达来减少组蛋白乙酰化。HDACis（TSA/SAHA）治疗显着抑制RSV复制并减少RSV诱导的气道炎症和氧化应激。因此，HDAC的抑制代表了调节RSV诱导的肺部疾病的新的治疗方法。
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. However, the majority of RSV-infected patients only show mild symptoms. Different severities of infection and responses among the RSV-infected population indicate that epigenetic regulation as well as personal genetic background may affect RSV infectivity. Histone deacetylase (HDAC) is an important epigenetic regulator in lung diseases. The present study aimed to explore the possible connection between HDAC expression and RSV-induced lung inflammation. To address this question, RSV-infected airway epithelial cells (BEAS-2B) were prepared and a mouse model of RSV infection was established, and then treated with various concentrations of HDAC inhibitors (HDACis), namely trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). Viral replication and markers of virus-induced airway inflammation or oxidative stress were assessed. The activation of the nuclear factor-κB (NF-κB), cyclo-oxygenase-2 (COX-2), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathways was evaluated by western blot analysis. Our results showed that RSV infection in airway epithelial cells (AECs) significantly decreased histone acetylation levels by altering HDAC2 expression. The treatment of RSV-infected AECs with HDACis significantly restricted RSV replication by upregulating the interferon-α (IFN-α) related signaling pathways. The treatment of RSV-infected AECs with HDACis also significantly inhibited RSV-induced pro-inflammatory cytokine release [interleukin (IL)-6 and IL-8] and oxidative stress-related molecule production [malondialdehyde (MDA), and nitrogen monoxide (NO)]. The activation of NF-κB, COX-2, MAPK and Stat3, which orchestrate pro-inflammatory gene expression and oxidative stress injury, was also significantly inhibited. Our in vivo study using a mouse model of RSV infection validated these results. Treatment with HDACis alleviated airway inflammation and reduced in vivo RSV replication. Our data demonstrated that RSV reduced histone acetylation by enhancing HDAC2 expression. Treatment with HDACis (TSA/SAHA) significantly inhibited RSV replication and decreased RSV-induced airway inflammation and oxidative stress. Therefore, the inhibition of HDACs represents a novel therapeutic approach in modulating RSV-induced lung disease.