Repeated lipopolysaccharide exposure causes corticosteroid insensitive airway inflammation via activation of phosphoinositide-3-kinase δ pathway

File Description SizeFormat 
1-s2.0-S2405580816301285-main.pdfPublished version645.24 kBAdobe PDFView/Open
Title: Repeated lipopolysaccharide exposure causes corticosteroid insensitive airway inflammation via activation of phosphoinositide-3-kinase δ pathway
Authors: Ueda, K
Nishimoto, Y
Kimura, G
Masuko, T
Barnes, PJ
Ito, K
Kizawa, Y
Item Type: Journal Article
Abstract: Corticosteroid resistance is one of major barriers to effective management of chronic inflammatory respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and severe asthma. These patients often experience exacerbations with viral and/or bacterial infection, which may cause continuous corticosteroid insensitive inflammation. In this study, we observed that repeated exposure of lipopolysaccharide (LPS) intranasally attenuated the anti-inflammatory effects of the corticosteroid fluticasone propionate (FP) on neutrophils and CXCL1 levels in bronchoalveolar lavage (BAL) fluid in an in vivo murine model. Histone deacetylase-2 (HDAC2) and NF-E2 related factor 2 (Nrf2) levels in lungs after LPS administration for 3 consecutive days were significantly decreased to 38.9±6.3% (mean±SEM) and 77.5±2.7% of the levels seen after only one day of LPS exposure, respectively. In addition, 3 days LPS exposure resulted in an increase of Akt phosphorylation, indicating activation of the phosphoinositide-3-kinase (PI3K) pathway by 4-fold in lungs compared with 1 day of exposure. Furthermore, combination treatment with theophylline and FP significantly decreased the neutrophil accumulation and CXCL1 concentrations in BAL fluid from 22.5±1.8×10 4 cells/mL and 214.6±20.6 pg/mL to 7.9±0.5×10 4 cells/mL and 61.9±13.3 pg/mL, respectively. Combination treatment with IC87114, a selective PI3Kδ inhibitor, and FP also significantly decreased neutrophils and CXCL1 levels from 16.8±0.7×10 4 cells/mL and 182.4±4.6 pg/mL to 5.9±0.3×10 4 cells/mL and 71.4±2.7 pg/mL, respectively. Taken together, repeated exposure of LPS causes corticosteroid-insensitive airway inflammation in vivo, and the corticosteroid-resistance induced by LPS is at least partly mediated through the activation of PI3Kδ, resulting in decreased levels of HDAC2 and Nrf2. These findings provide a potentially new therapeutic approach to COPD and severe asthma.
Issue Date: 1-Sep-2016
Date of Acceptance: 19-Jul-2016
ISSN: 2405-5808
Publisher: Elsevier
Start Page: 367
End Page: 373
Journal / Book Title: Biochemistry and Biophysics Reports
Volume: 7
Copyright Statement: © 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Creative Commonsx