TY - JOUR
T1 - Repeated lipopolysaccharide exposure causes corticosteroid insensitive airway inflammation via activation of phosphoinositide-3-kinase δ pathway
AU - Ueda, Keitaro
AU - Nishimoto, Yuki
AU - Kimura, Genki
AU - Masuko, Takashi
AU - Barnes, Peter J.
AU - Ito, Kazuhiro
AU - Kizawa, Yasuo
N1 - Publisher Copyright:
© 2016 The Authors
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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±1.8×104 cells/mL and 214.6±20.6 pg/mL to 7.9±0.5×104 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±0.7×104 cells/mL and 182.4±4.6 pg/mL to 5.9±0.3×104 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.
AB - 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±1.8×104 cells/mL and 214.6±20.6 pg/mL to 7.9±0.5×104 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±0.7×104 cells/mL and 182.4±4.6 pg/mL to 5.9±0.3×104 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.
KW - Airway inflammation
KW - COPD
KW - Corticosteroid-resistance
KW - HDAC2
KW - PI3K Nrf2
UR - http://www.scopus.com/inward/record.url?scp=84982684960&partnerID=8YFLogxK
U2 - 10.1016/j.bbrep.2016.07.020
DO - 10.1016/j.bbrep.2016.07.020
M3 - Article
AN - SCOPUS:84982684960
SN - 2405-5808
VL - 7
SP - 367
EP - 373
JO - Biochemistry and Biophysics Reports
JF - Biochemistry and Biophysics Reports
ER -