Inhibition of histone-deacetylase activity rescues inflammatory cystic fibrosis lung disease by modulating innate and adaptive immune responses.
Inhibition of histone-deacetylase activity rescues inflammatory cystic fibrosis lung disease by modulating innate and adaptive immune responses.
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DOI：
10.1186/s12931-017-0705-8
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发表时间：
2018-01-04
影响因子：
5.8
通讯作者：
Vij N
中科院分区：
文献类型：
--
作者：
Bodas M;Mazur S;Min T;Vij N
由功能失调的囊性纤维化跨膜传导调节因子（CFTR）和nf κ b介导的中性粒细胞炎症引起的慢性肺部疾病是cf相关死亡率的基础。在这里，我们旨在评估HDAC抑制是否控制铜绿假单胞菌脂多糖（Pa-LPS）诱导的气道炎症和cf -肺部疾病。在体外实验中，hek293细胞转染IL-8或nfκ b萤火虫荧光素酶，sv40 -肾荧光素酶报告基因构建物或ΔF508-CFTR-pCEP，然后用亚eroylanilide羟肟酸（SAHA）、Trichostatin-A （TSA）和/或TNFα处理。在小鼠研究中，Cftr+/+或Cftr−/−小鼠（n = 3）被注射/灌注Pa-LPS和/或SAHA或对照。通过量化炎症标志物（NFκB）、细胞因子（IL-6/IL-10）、中性粒细胞活性（MPO、髓过氧化物酶和/或NIMP-R14）和T-reg数量的变化来监测肺部疾病的进展。SAHA处理显著（p < 0.05）抑制tnf α诱导的hek293细胞nf - κ b和IL-8报告细胞活性。此外，SAHA, Tubacin（选择性hdac6抑制剂）或HDAC6-shRNAs控制cse诱导的er应激活性（p < 0.05）。此外，SAHA通过诱导CFTR的B和C形式的蛋白水平来恢复错误折叠-ΔF508-CFTR的运输。使用Cftr+/+或Cftr−/−小鼠进行的小鼠研究证实，SAHA控制Pa-LPS诱导的IL-6水平、中性粒细胞（MPO水平和/或NIMP-R14）、NFκB-（炎症）和Nrf2（氧化应激标志物）活性，同时促进FoxP3+ T-reg活性。综上所述，saha介导的HDAC抑制调节了参与炎性cf -肺病发病和进展的先天和适应性免疫反应。本文的在线版本（10.1186/s12931-017-0705-8）包含补充材料，授权用户可使用。
Chronic lung disease resulting from dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) and NFκB-mediated neutrophilic-inflammation forms the basis of CF-related mortality. Here we aimed to evaluate if HDAC inhibition controls Pseudomonas-aeruginosa-lipopolysaccharide (Pa-LPS) induced airway inflammation and CF-lung disease. For in vitro experiments, HEK293-cells were transfected with IL-8 or NFκB-firefly luciferase, and SV40-renilla- luciferase reporter constructs or ΔF508-CFTR-pCEP, followed by treatment with suberoylanilide hydroxamic acid (SAHA), Trichostatin-A (TSA) and/or TNFα. For murine studies, Cftr+/+ or Cftr−/− mice (n = 3) were injected/instilled with Pa-LPS and/or treated with SAHA or vehicle control. The progression of lung disease was monitored by quantifying changes in inflammatory markers (NFκB), cytokines (IL-6/IL-10), neutrophil activity (MPO, myeloperoxidase and/or NIMP-R14) and T-reg numbers. SAHA treatment significantly (p < 0.05) suppresses TNFα-induced NFκB and IL-8 reporter activities in HEK293-cells. Moreover, SAHA, Tubacin (selective HDAC6-inhibitor) or HDAC6-shRNAs controls CSE-induced ER-stress activities (p < 0.05). In addition, SAHA restores trafficking of misfolded-ΔF508-CFTR, by inducing protein levels of both B and C forms of CFTR. Murine studies using Cftr+/+ or Cftr−/− mice verified that SAHA controls Pa-LPS induced IL-6 levels, and neutrophil (MPO levels and/or NIMP-R14), NFκB-(inflammation) and Nrf2 (oxidative-stress marker) activities, while promoting FoxP3+ T-reg activity. In summary, SAHA-mediated HDAC inhibition modulates innate and adaptive immune responses involved in pathogenesis and progression of inflammatory CF-lung disease. The online version of this article (10.1186/s12931-017-0705-8) contains supplementary material, which is available to authorized users.
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影响因子：
4.2
作者：
Hutt, Darren M.;Olsen, Christian A.;Ghadiri, M. Reza
通讯作者：
Ghadiri, M. Reza
影响因子：
7.2
作者：
Bodas, Manish;Min, Taehong;Vij, Neeraj
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影响因子：
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通讯作者：
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影响因子：
4.7
作者：
Min, Taehong;Bodas, Manish;Mazur, Steven;Vij, Neeraj
通讯作者：
Vij, Neeraj
影响因子：
3.7
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通讯作者：
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