PI3Kγ-deficient mice have reduced levels of allergen-induced eosinophilic inflammation and airway remodeling
PI3Kγ-deficient mice have reduced levels of allergen-induced eosinophilic inflammation and airway remodeling
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DOI：
10.1152/ajplung.90275.2008
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发表时间：
2009-02-01
影响因子：
4.9
通讯作者：
Broide, David H.
中科院分区：
文献类型：
--
作者：
Lim, Dae Hyun;Cho, Jae Youn;Broide, David H.
Lim DH、Cho JY、Song DJ、Lee SY、Miller M、Broide DH。 PI3K γ 缺陷小鼠的过敏原诱导的嗜酸性粒细胞炎症和气道重塑水平降低。 Am J Physiol Lung Cell Mol Physiol 296: L210-L219, 2009。首次发表于 2008 年 11 月 21 日； doi:10.1152/ajplung.90275.2008.-在这项研究中，我们研究了磷酸肌醇 3 激酶 γ (PI3K γ)（Ib 类 PI3K）在利用暴露于慢性过敏原攻击的 PI3K γ 缺陷小鼠进行气道重塑中的作用。对卵清蛋白 (OVA) 敏感并长期接受 OVA 1 个月的野生型 (WT) 小鼠，嗜酸性粒细胞炎症和气道重塑水平显着增加。相反，与 WT 小鼠相比，用 OVA 攻击的 PI3K γ 缺陷小鼠的支气管肺泡灌洗液和支气管周围嗜酸性粒细胞的数量显着减少。当比较WT小鼠和PI3Kγ缺陷小鼠时，骨髓或循环外周血嗜酸性粒细胞的数量没有显着差异，这表明PI3Kγ缺陷小鼠中嗜酸性粒细胞进入肺部的运输减少。 PI3K γ 缺陷小鼠和 WT 小鼠的 IL-5 和嗜酸细胞活化趋化因子 1 水平相似。在接受 OVA 攻击的 PI3K γ 缺陷小鼠中，气道中嗜酸性粒细胞募集的减少与 TGF-β 1 + 支气管周围细胞数量的显着减少、pSmad 2/3 + 气道上皮细胞和 pSmad 2/3 + 支气管周围细胞数量的减少以及支气管周围纤维化水平的显着降低有关（通过三色染色和图像分析以及肺胶原水平进行定量）。此外，与 WT 小鼠相比，PI3K gamma 缺陷小鼠的支气管周围 α 平滑肌染色面积显着减少。总体而言，本研究证明 PI3K γ 在介导过敏原诱导的嗜酸性粒细胞气道炎症和气道重塑中发挥重要作用，表明 PI3K γ 可能是哮喘的新治疗靶点。
Lim DH, Cho JY, Song DJ, Lee SY, Miller M, Broide DH. PI3K gamma-deficient mice have reduced levels of allergen-induced eosinophilic inflammation and airway remodeling. Am J Physiol Lung Cell Mol Physiol 296: L210-L219, 2009. First published November 21, 2008; doi:10.1152/ajplung.90275.2008.-In this study, we have examined the role of phosphoinositide 3 kinase gamma (PI3K gamma), a class Ib PI3K, in contributing to airway remodeling utilizing PI3K gamma-deficient mice exposed to chronic allergen challenge. Wild-type (WT) mice sensitized to ovalbumin ( OVA) and chronically challenged with OVA for 1 mo developed significantly increased levels of eosinophilic inflammation and airway remodeling. In contrast, PI3K gamma-deficient mice challenged with OVA had significantly reduced numbers of bronchoalveolar lavage and peribronchial eosinophils compared with WT mice. There was no significant difference in the number of bone marrow or circulating peripheral blood eosinophils when comparing WT mice and PI3K gamma-deficient mice, suggesting that trafficking of eosinophils into the lung was reduced in PI3K gamma-deficient mice. PI3K gamma-deficient and WT mice had similar levels of IL-5 and eotaxin-1. The reduced eosinophil recruitment to the airway in PI3K gamma-deficient mice challenged with OVA was associated with significantly reduced numbers of TGF-beta 1 + peribronchial cells, reduced numbers of pSmad 2/3 + airway epithelial cells, and pSmad 2/3 + peribronchial cells, as well as significantly reduced levels of peribronchial fibrosis (quantitated by trichrome staining and image analysis as well as by lung collagen levels). In addition, the area of peribronchial alpha-smooth muscle staining was significantly reduced in PI3K gamma-deficient compared with WT mice. Overall, this study demonstrates an important role for PI3K gamma in mediating allergen-induced eosinophilic airway inflammation and airway remodeling, suggesting that PI3K gamma may be a novel therapeutic target in asthma.