Ito Kazuhiro, Herbert Cristan, Siegle Jessica S, Vuppusetty Chaitanya, Hansbro Nicole, Thomas Paul S, Foster Paul S, Barnes Peter J, Kumar Rakesh K
Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK.
Am J Respir Cell Mol Biol. 2008 Nov;39(5):543-50. doi: 10.1165/rcmb.2008-0028OC. Epub 2008 May 12.
Neutrophilic inflammation in acute exacerbations of asthma tends to be resistant to treatment with glucocorticoids. This may be related to decreased activity and expression of histone deacetylase-2 (HDAC2), which down-regulates expression of proinflammatory genes via recruitment to the glucocorticoid receptor complex. We assessed airway inflammation and response to steroid treatment in a novel mouse model of an acute exacerbation of chronic asthma. Systemically sensitized mice received low-level challenge with aerosolized ovalbumin for 4 weeks, followed by a single moderate-level challenge to induce enhanced inflammation in distal airways. We assessed the effects of pre-treatment with dexamethasone on the accumulation of inflammatory cells in the airways, airway responsiveness to methacholine, expression and enzymatic activity of nuclear proteins including histone acetyl transferase (HAT) and HDAC2, and levels of transcripts for neutrophil chemoattractant and survival cytokines. Dexamethasone suppressed inflammation associated with eosinophil and T-lymphocyte recruitment, but did not prevent neutrophil accumulation or development of airway hyperresponsiveness. Increased activity of HAT was suppressed by steroid treatment, but the marked diminution of HDAC2 activity and increased activity of nuclear factor-kappaB were not reversed. Correspondingly, elevated expression of mRNA for TNF-alpha, granulocyte-macrophage colony-stimulating factor, IL-8, and p21(waf) were also not suppressed by dexamethasone. Levels of lipid peroxidation and protein nitration products were elevated in the acute exacerbation model. We conclude that impaired nuclear recruitment of HDAC2 could be an important mechanism of steroid resistance of the neutrophilic inflammation in exacerbations of asthma. Oxidative stress may contribute to decreased HDAC2 activity.
哮喘急性加重期的中性粒细胞炎症往往对糖皮质激素治疗有抵抗性。这可能与组蛋白去乙酰化酶2（HDAC2）的活性和表达降低有关，HDAC2通过募集到糖皮质激素受体复合物来下调促炎基因的表达。我们在一种新型慢性哮喘急性加重小鼠模型中评估了气道炎症和对类固醇治疗的反应。全身致敏的小鼠接受雾化卵清蛋白低水平激发4周，随后进行单次中等水平激发以诱导远端气道炎症增强。我们评估了地塞米松预处理对气道中炎症细胞积聚、气道对乙酰甲胆碱的反应性、包括组蛋白乙酰转移酶（HAT）和HDAC2在内的核蛋白的表达和酶活性，以及中性粒细胞趋化因子和存活细胞因子转录水平的影响。地塞米松抑制了与嗜酸性粒细胞和T淋巴细胞募集相关的炎症，但未能阻止中性粒细胞积聚或气道高反应性的发展。类固醇治疗抑制了HAT活性的增加，但HDAC2活性的显著降低和核因子-κB活性的增加并未得到逆转。相应地，地塞米松也未抑制肿瘤坏死因子-α、粒细胞-巨噬细胞集落刺激因子、白细胞介素-8和p21（waf）的mRNA表达升高。急性加重模型中脂质过氧化和蛋白质硝化产物水平升高。我们得出结论，HDAC2的核募集受损可能是哮喘加重期中性粒细胞炎症类固醇抵抗的重要机制。氧化应激可能导致HDAC2活性降低。
