Treatment with 1,25(OH)2D3 induced HDAC2 expression and reduced NF-κB p65 expression in a rat model of OVA-induced asthma

Recent evidence indicates that a deficiency of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) may influence asthma pathogenesis; however, its roles in regulating specific molecular transcription mechanisms remain unclear. We aimed to investigate the effect of 1,25(OH)2D3 on the expression and enzyme activity of histone deacetylase 2 (HDAC2) and its synergistic effects with dexamethasone (Dx) in the inhibition of inflammatory cytokine secretion in a rat asthma model. Healthy Wistar rats were randomly divided into 6 groups: control, asthma, 1,25(OH)2D3 pretreatment, 1,25(OH)2D3 treatment, Dx treatment, and Dx and 1,25(OH)2D3 treatment. Pulmonary inflammation was induced by ovalbumin (OVA) sensitization and challenge (OVA/OVA). Inflammatory cells and cytokines in the bronchoalveolar lavage (BAL) fluid and histological changes in lung tissue were examined. Nuclear factor kappa B (NF-κB) p65 and HDAC2 expression levels were assessed with Western blot analyses and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Enzyme activity measurements and immunohistochemical detection of HDAC2 were also performed. Our data demonstrated that 1,25(OH)2D3 reduced the airway inflammatory response and the level of inflammatory cytokines in BAL. Although NF-κB p65 expression was attenuated in the pretreatment and treatment groups, the expression and enzyme activity of HDAC2 were increased. In addition, 1,25(OH)2D3 and Dx had synergistic effects on the suppression of total cell infusion, cytokine release, and NF-κB p65 expression, and they also increased HDAC2 expression and activity in OVA/OVA rats. Collectively, our results indicated that 1,25(OH)2D3 might be useful as a novel HDAC2 activator in the treatment of asthma.

最新研究证据表明，1,25-二羟基维生素D3（1,25(OH)2D3）缺乏可能影响哮喘发病机制，但其调控特定分子转录机制的作用仍未明确。本研究旨在探讨1,25(OH)2D3对大鼠哮喘模型中组蛋白去乙酰化酶2（HDAC2）的表达与酶活性的影响，及其与地塞米松（Dx）协同抑制炎症因子分泌的效应。将健康Wistar大鼠随机分为6组：对照组、哮喘模型组、1,25(OH)2D3预处理组、1,25(OH)2D3治疗组、地塞米松治疗组，以及地塞米松联合1,25(OH)2D3治疗组。采用卵清蛋白（OVA）致敏与激发（OVA/OVA）方案诱导肺部炎症。收集支气管肺泡灌洗液（BAL液）检测炎症细胞与细胞因子水平，观察肺组织病理学改变；通过蛋白质免疫印迹（Western blot）与定量反转录聚合酶链反应（qRT-PCR）检测核因子κB（NF-κB）p65及HDAC2的表达水平；同时开展酶活性测定与HDAC2免疫组化检测。研究结果显示，1,25(OH)2D3可降低BAL液中的气道炎症反应与炎症因子水平。尽管预处理组与治疗组的NF-κB p65表达均被下调，但HDAC2的表达与酶活性均有所升高。此外，1,25(OH)2D3与地塞米松在抑制总细胞浸润、细胞因子释放及NF-κB p65表达方面具有协同效应，同时可上调OVA/OVA模型大鼠的HDAC2表达与活性。综上，本研究结果提示1,25(OH)2D3有望作为新型HDAC2激活剂用于哮喘的治疗。