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PI3Kδ 在慢性阻塞性肺疾病患者糖皮质激素反应受损中的作用。

A role for phosphoinositol 3-kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease.

机构信息

Centro di Ricerca su Asma e BPCO, Università di Ferrara, Ferrara, Italy.

出版信息

J Allergy Clin Immunol. 2010 May;125(5):1146-53. doi: 10.1016/j.jaci.2010.02.003. Epub 2010 Apr 9.

Abstract

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) delta signaling.

OBJECTIVE

We sought to determine the role of PI3Kdelta 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 PI3Kdelta 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 PI3Kdelta but not PI3Kgamma. 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 PI3Kdelta but not PI3Kgamma.

CONCLUSION

PI3Kdelta expression and signaling is increased in the lungs of patients with COPD. Selective inhibition of PI3Kdelta might restore glucocorticoid function in patients with COPD and might therefore present a potential therapeutic target.

摘要

背景

慢性阻塞性肺疾病(COPD)患者的肺部糖皮质激素功能明显受损。这种糖皮质激素敏感性的降低可能是由于氧化应激介导的磷酸肌醇 3-激酶(PI3K)δ信号的增加。

目的

我们旨在确定 PI3Kδ在 COPD 患者糖皮质激素反应降低中的作用。

方法

从 24 例 COPD 患者、20 例年龄匹配的肺功能正常的吸烟者和 13 例非吸烟者中获得外周肺组织。从 9 例 COPD 患者和 7 例年龄匹配的肺功能正常的吸烟者以及健康志愿者中分离外周血单核细胞。

结果

与年龄匹配的吸烟者和非吸烟者对照组相比,COPD 患者的巨噬细胞中 PI3Kδ和 Akt 磷酸化表达增加。体外氧化应激诱导单核细胞和巨噬细胞中 Akt 的磷酸化,这一过程可被 PI3Kδ的选择性抑制而不是 PI3Kγ所阻断。与年龄匹配的吸烟者相比,地塞米松对 COPD 患者血液单核细胞中 LPS 诱导的 GM-CSF 和 CXC 趋化因子 8 释放的抑制作用较弱。这种低敏感性可通过抑制 PI3Kδ而不是 PI3Kγ得到逆转。

结论

PI3Kδ的表达和信号在 COPD 患者的肺部增加。PI3Kδ的选择性抑制可能恢复 COPD 患者的糖皮质激素功能,因此可能成为一个潜在的治疗靶点。

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