Reversal of corticosteroid insensitivity in COPD by theophylline

慢性阻塞性肺疾病（COPD）还是吸烟者？肺是一个日益严重的问题，已经是英国最常见的死亡和残疾原因之一。慢性阻塞性肺病造成的直接医疗费用超过8亿美元。慢性阻塞性肺病与肺部炎症有关，随着疾病的进展，炎症会恶化。哮喘还包括肺部炎症，但这通常很容易用类固醇吸入器控制，这是一种非常有效的治疗方法。相比之下，COPD中的炎症对类固醇治疗没有反应，我们已经证明COPD患者的细胞也没有反应，这表明这个问题可能是由于分子缺陷。类固醇的作用是通过细胞核中一种叫做组蛋白去乙酰酶-2 （HDAC2）的酶来关闭编码炎症产物的基因。我们已经证明，慢性阻塞性肺病患者的肺和细胞中的HDAC2受损，因此类固醇不再能够关闭炎症。我们发现茶碱，一种用于治疗哮喘的老药物，能够激活HDAC2并使其水平恢复正常，从而逆转COPD患者细胞中的类固醇抵抗。我们现在计划在慢性阻塞性肺病患者中进行试验，给他们低剂量的茶碱，看看这是否允许吸入类固醇来控制炎症。我们还计划研究茶碱是如何激活这些细胞中的HDAC的，因为这可能会在未来带来新的治疗方法。由于目前还没有治疗慢性阻塞性肺病的抗炎治疗方法，而且戒烟似乎对炎症几乎没有影响，因此迫切需要找到可能逆转慢性阻塞性肺病类固醇耐药性的治疗方法或寻找替代抗炎药物。

Chronic obstructive pulmonary disease (COPD) or smokers? lung is a growing problem and already one of the commonest causes of death and disability in the UK. COPD accounts for over #800 million in direct healthcare costs. COPD is associated with inflammation in the lung, which gets worse as the disease progresses. Asthma also involves inflammation in the lung but this is usually easy to control with steroid inhalers, which are very effective treatment. By contrast, the inflammation in COPD does not respond to steroid therapy and we have shown that cells from COPD patients also fail to respond, indicating that this problem is likely to be due to a molecular defect. Steroids work by switching off genes that code for inflammatory products by an enzyme in the nucleus called histone deacetylase-2 (HDAC2). We have shown that HDAC2 is impaired in the lungs and cells of COPD patients, so that steroids can no longer switch off inflammation. We have found that theophylline, an old drug used to treat asthma, is able to active HDAC2 and restore its levels to normal, thus reversing steroid resistance in cells from COPD patients. We now plan to test this in patients with COPD by giving low doses of theophylline to see whether this allows inhaled steroids to control inflammation. We also plan to look into how theophylline is able to active HDAC in these cells, as this might lead to new treatments in the future. As no anti-inflammatory treatments currently exist for the treatment of COPD and stopping smoking does appear to little or no effect on the inflammation, there is an urgent need to find treatments that may reverse steroid resistance in COPD or to find alternative anti-inflammatory drugs.