An anti-inflammatory role for a phosphoinositide 3-kinase inhibitor LY294002 in a mouse asthma model

被引:100
作者
Duan, W
Datiles, AMKA
Leung, BP
Vlahos, CJ
Wong, WSF
机构
[1] Natl Univ Singapore, Fac Med, Dept Pharmacol, Singapore 117597, Singapore
[2] Natl Univ Singapore, Dept Physiol, Singapore 117597, Singapore
[3] Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA
关键词
ovalbumin; airway hyperresponsiveness; Eosinophilia; mucus hypersecretion; Akt;
D O I
10.1016/j.intimp.2004.10.015
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Phosphomositide 3-kinase (PI3K) exhibits broad functional effects in immune cells. We investigated the role of PI3K in allergic airway inflammation using LY294002, a specific PI3K inhibitor, in a mouse asthma model. BALB/c mice were sensitized and challenged with ovalbumin (OVA), and developed airway eosinophilia, mucus hypersecretion, elevation in cytokine levels, and airway hyperresponsiveness. Intratracheal administration of LY294002 significantly inhibited OVA-induced increases in total cell counts, eosinophil counts, and IL-5, IL-13, and eotaxin levels in bronchoalveolar lavage fluid. Histological studies show that LY294002 dramatically inhibited OVA-induced lung tissue eosinophilia and air-way mucus production. In addition, LY294002 significantly suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine. Western blot analysis of whole lung lysates shows that LY294002 markedly attenuated OVA-induced serine phosphorylation of Akt, a direct downstream substrate of PI3K. Taken together, our findings suggest that inhibition of PI3K signaling pathway can suppress T-helper type 2 (Th2) cytokine production, eosinophil infiltration, mucus production, and airway hyperresponsiveness in a mouse asthma model and may have therapeutic potential for the treatment of allergic airway inflammation. (C) 2004 Elsevier B.V. All rights reserved.
引用
收藏
页码:495 / 502
页数:8
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