Marwick John A, Caramori Gaetano, Stevenson Christopher S, Casolari Paolo, Jazrawi Elen, Barnes Peter J, Ito Kazuhiro, Adcock Ian M, Kirkham Paul A, Papi Alberto
Airways Disease Section, National Heart & Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK.
Am J Respir Crit Care Med. 2009 Apr 1;179(7):542-8. doi: 10.1164/rccm.200810-1570OC. Epub 2009 Jan 22.
There is an increasing prevalence of reduced responsiveness to glucocorticoid therapy in severe asthma and chronic obstructive pulmonary disease (COPD). The molecular mechanism of this remains unknown. Recent studies have shown that histone deacetylase activity, which is critical to glucocorticoid function, is altered by oxidant stress and may be involved in the development of glucocorticoid insensitivity.
To determine the role of phosphoinositol-3-kinase (PI3K) in the development of cigarette smoke-induced glucocorticoid insensitivity.
Wild-type, PI3Kgamma knock-out and PI3Kdelta kinase dead knock-in transgenic mice were used in a model of cigarette smoke-induced glucocorticoid insensitivity. Peripheral lung tissue was obtained from six healthy nonsmokers, nine smokers with normal lung function, and eight patients with COPD.
In vitro oxidative stress activates PI3K and induced a relative glucocorticoid resistance, which is restored by PI3K inhibition. In vivo, cigarette smoke exposure in mice increased tyrosine nitration of histone deacetylase 2 in the lung, correlating with reduced histone deacetylase 2 activity and reduced glucocorticoid function. Histone deacetylase 2 activity and the antiinflammatory effects of glucocorticoids were restored in PI3Kdelta kinase dead knock-in but not PI3Kgamma knock-out smoke-exposed mice compared with wild type mice, correlating with reduced histone deacetylase 2 tyrosine nitration. Glucocorticoid receptor expression was significantly reduced in smoke-exposed mice, in smokers with normal lung function, and in patients with COPD.
These data show that therapeutic inhibition of PI3Kdelta may restore glucocorticoid function in oxidative stress-induced glucocorticoid insensitivity.
在重度哮喘和慢性阻塞性肺疾病（COPD）中，对糖皮质激素治疗反应性降低的情况日益普遍。其分子机制尚不清楚。最近的研究表明，对糖皮质激素功能至关重要的组蛋白脱乙酰酶活性会因氧化应激而改变，可能参与了糖皮质激素不敏感的发生发展。
确定磷酸肌醇-3-激酶（PI3K）在香烟烟雾诱导的糖皮质激素不敏感发生发展中的作用。
将野生型、PI3Kγ基因敲除和PI3Kδ激酶失活的基因敲入转基因小鼠用于香烟烟雾诱导的糖皮质激素不敏感模型。从6名健康非吸烟者、9名肺功能正常的吸烟者和8名COPD患者获取外周肺组织。
体外氧化应激激活PI3K并诱导相对糖皮质激素抵抗，PI3K抑制可使其恢复。在体内，小鼠暴露于香烟烟雾会增加肺中组蛋白脱乙酰酶2的酪氨酸硝化，这与组蛋白脱乙酰酶2活性降低和糖皮质激素功能降低相关。与野生型小鼠相比，PI3Kδ激酶失活的基因敲入但不是PI3Kγ基因敲除的烟雾暴露小鼠中，组蛋白脱乙酰酶2活性和糖皮质激素的抗炎作用得以恢复，这与组蛋白脱乙酰酶2酪氨酸硝化减少相关。糖皮质激素受体表达在烟雾暴露小鼠、肺功能正常的吸烟者和COPD患者中显著降低。
这些数据表明，治疗性抑制PI3Kδ可能恢复氧化应激诱导的糖皮质激素不敏感中的糖皮质激素功能。
