Theophylline in chronic obstructive pulmonary disease: new horizons.
Theophylline in chronic obstructive pulmonary disease: new horizons.
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DOI：
10.1513/pats.200504-024sr
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发表时间：
2005-01-01
期刊：
影响因子：
--
通讯作者：
Barnes, Peter J
中科院分区：
文献类型：
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作者：
Barnes, Peter J
尽管茶碱在支气管扩张剂剂量下使用时会产生副作用，但越来越多的证据表明，茶碱在较低血浆浓度下对慢性阻塞性肺疾病具有显着的抗炎作用。这些抗炎作用不太可能是通过磷酸二酯酶抑制或腺苷受体拮抗作用来解释的，因为这需要更高的浓度。现在有证据表明，低治疗浓度的茶碱是组蛋白脱乙酰酶的激活剂，并且这种激活增强了皮质类固醇的抗炎作用。慢性阻塞性肺疾病患者的巨噬细胞和外周肺中的组蛋白脱乙酰酶 2 似乎显着减少，这是炎症和类固醇抵抗加剧的原因。茶碱已被证明可以在体外恢复类固醇敏感性。氧化应激似乎增强了茶碱对组蛋白脱乙酰酶活性的影响。茶碱激活组蛋白脱乙酰酶的机制尚不清楚，但不涉及茶碱其他已知的导致其副作用的作用。更好地了解茶碱作用的分子基础可能会导致新药的开发。
Although theophylline has side effects when used in bronchodilator doses, increasing evidence shows that it has significant antiinflammatory effects in chronic obstructive pulmonary disease at lower plasma concentrations. These antiinflammatory effects are unlikely to be accounted for by phosphodiesterase inhibition or adenosine receptor antagonism, which require higher concentrations. There is now evidence that theophylline at low therapeutic concentrations is an activator of histone deacetylases and that this activation enhances the antiinflammatory effect of corticosteroids. There appears to be a marked reduction in histone deacetylase-2 in macrophages and peripheral lung of patients with chronic obstructive pulmonary disease, which accounts for amplified inflammation and steroid resistance. Theophylline has been shown to restore steroid sensitivity in vitro. The effect of theophylline on histone deacetylase activity appears to be enhanced by oxidative stress. The mechanism whereby theophylline activates histone deacetylase is not yet known, but it does not involve other known actions of theophylline that account for its side effects. Better understanding of the molecular basis for the action of theophylline might lead to the development of novel drugs.