Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs
Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs
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DOI：
10.1165/rcmb.2004-0006oc
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发表时间：
2004-12-01
影响因子：
6.4
通讯作者：
Rahman, I
中科院分区：
文献类型：
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作者：
Marwick, JA;Kirkham, PA;Rahman, I
香烟烟雾引发的炎症被认为在慢性阻塞性肺疾病的发展中发挥核心作用，其机制可能涉及促炎基因转录的增强。组蛋白乙酰化和去乙酰化是基因转录的特异性和持续时间的关键调节因子。核组蛋白乙酰化：去乙酰化平衡的破坏（染色质重塑）可能导致肺中特定促炎基因的过度转录。在这项研究中，我们表明，香烟烟雾暴露的结果在大鼠肺炎症细胞和染色质修饰的流入。这与p38丝裂原活化蛋白激酶的活性磷酸化形式增加，同时组蛋白3磷酸乙酰化、组蛋白4乙酰化增加，以及氧化还原敏感性转录因子核因子-kappaB的DNA结合增加（独立于抑制性蛋白-kappaB降解和激活蛋白1）有关。我们还观察到组蛋白去乙酰化酶2活性降低，这是由于香烟烟雾中存在的醛和一氧化氮产物对蛋白质的修饰。此外，我们发现皮质类固醇治疗对烟雾诱导的促炎介质释放没有影响。这些发现表明，香烟烟雾驱动促炎基因转录和肺部炎症反应的可能分子机制。
Cigarette smoke-triggered inflammation is considered to play a central role in the development of chronic obstructive pulmonary disease by a mechanism that may involve enhanced proinflammatory gene transcription. Histone acetylation and deacetylation is a key regulator of the specificity and duration of gene transcription. Disruption in the nuclear histone acetylation:deacetylation balance (chromatin remodeling) may result in excessive transcription of specific proinflammatory genes in the lungs. In this study we show that cigarette smoke exposure results in an influx of inflammatory cells and chromatin modifications in rat lungs. This was associated with an increase in the active phosphorylated form of p38 mitogen-activated protein kinase concomitant with increased histone 3 phospho-acetylation, histone 4 acetylation, and increased DNA binding of the redox-sensitive transcription factor nuclear factor-kappaB, independent of inhibitory protein-kappaB degradation, and activator protein 1. We also observed decreased histone deacetylase 2 activity, which is due to protein modification by aldehydes and nitric oxide products present in cigarette smoke. Furthermore, we show that corticosteroid treatment has no effect on smoke-induced proinflammatory mediator release. These findings suggest a possible molecular mechanism by which cigarette smoke drives proinflammatory gene transcription and an inflammatory response in the lungs.