脂多糖
肺
支气管肺泡灌洗
医学
炎症
化学
蛋白激酶B
紧密连接
免疫学
气道
髓过氧化物酶
药理学
肿瘤坏死因子α
封堵器
促炎细胞因子
卵清蛋白
PI3K/AKT/mTOR通路
作者
Le Yao,Ying Tang,Junjie Chen,Jiahui Li,Hua Wang,Lu Ming,Lijuan Gao,Fang Liu,Ping Chang,Xingxing Liu,Haixiong Tang
标识
DOI:10.1016/j.intimp.2021.107570
摘要
Cell-cell junctions are critical for the maintenance of cellular as well as tissue polarity and integrity. Dysfunction of airway epithelial barrier has been shown to be involved in the pathogenesis of acute lung injury (ALI). Yet the role of phosphatidylinositol 3-kinase delta (PI3Kδ) in dysregulation of airway epithelial barrier integrity in ALI has not been addressed. Mice were subjected to intratracheal instillation of lipopolysaccharide (LPS) to generate a ALI model. Two pharmacological inhibitors of PI3Kδ, IC87114 and AMG319, were respectively given to the mice. Expression of p110δ and its downstream substrate phospho-AKT (Ser473) was increased in LPS-exposed lungs. These increases were inhibited by IC87114 or AMG319. LPS led to pronounced lung injury that was accompanied by significant airway neutrophil recruitment and bronchial epithelial morphological alterations 72 h after exposure. We also found compromised expression of adherens junction protein E-cadherin and tight junction protein claudin-2 in the airway epithelial cells. Treatment with either IC87114 or AMG319 not only attenuated LPS-induced edema, lung injury and neutrophilc inflammation, reduced total protein concentration and IL-6, TNF-α secretion in BALF, but also restored epithelial E-cadherin and claudin-2 expression. In summary, our results showed that LPS can induce a delayed effect on airway epithelial barrier integrity that is mediated by PI3Kδ in a mouse model of ALI.
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