- 作者：John A. Marwick ; Gaetano Caramori ; Paolo Casolari ; Federico Mazzoni ; Paul A. Kirkham ; Ian M. Adcock ; Kian Fan Chung ; Alberto Papi
- 关键词：Phosphoinositol 3– ; kinase ; oxidative stress ; Akt ; macrophage ; glucocorticoid insensitivity ; chronic obstructive disease
- 刊名：Journal of Allergy and Clinical Immunology
- 出版年：2010
- 出版时间：May 2010
- 年：2010
- 卷：125
- 期：5
- 页码：1146-1153
- 全文大小：887 K
Background
Glucocorticoid function is markedly impaired in the lungs of patients with chronic obstructive pulmonary disease (COPD). This reduction in glucocorticoid sensitivity might be due to an oxidant-mediated increase in phosphoinositol 3–kinase (PI3K) δ signaling.Objective
We sought to determine the role of PI3Kδ in the reduced glucocorticoid responsiveness in patients with COPD.
Methods
Peripheral lung tissue was obtained from 24 patients with COPD, 20 age-matched smokers with normal lung function, and 13 nonsmokers. Peripheral blood monocytes were isolated from 9 patients with COPD and 7 age-matched smokers with normal lung function and from healthy volunteers.
Results
The expressions of PI3Kδ and Akt phosphorylation were increased in macrophages from patients with COPD compared with those from control groups of age-matched smokers and nonsmokers. In vitro oxidative stress induced phosphorylation of Akt in monocytes and macrophages, which was abolished by means of selective inhibition of PI3Kδ but not PI3Kγ. Dexamethasone was less effective at repressing LPS-induced GM-CSF and CXC motif chemokine 8 release in blood monocytes from patients with COPD compared with age-matched smokers. This reduced sensitivity was reversed by inhibition of PI3Kδ but not PI3Kγ.
Conclusion
PI3Kδ expression and signaling is increased in the lungs of patients with COPD. Selective inhibition of PI3Kδ might restore glucocorticoid function in patients with COPD and might therefore present a potential therapeutic target.