RT Journal Article
SR Electronic
T1 PI3K inhibitor add-on strategy improve glucocorticoid insensitivity in severe asthma
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 2906
DO 10.1183/13993003.congress-2020.2906
VO 56
IS suppl 64
A1 Zhihong Chen
A1 Jin Bi
A1 Zhihui Min
A1 Chunling Du
YR 2020
UL http://erj.ersjournals.com/content/56/suppl_64/2906.abstract
AB Background: Glucocorticoid (GC) insensitivity is an important feature of severe and fatal asthma. Oxidative stress can induce phosphoinositide-3-kinase (PI3K) activation, contributing to the development of GC insensitivity in chronic airway diseases. However, the underlying molecular mechanism of PI3K in the pathogenesis of severe asthma remains unknown.Methods: We isolated peripheral blood mononuclear cells (PBMCs) from 34 participants (12 patients with mild/moderate asthma, 10 patients with severe asthma, and 12 control subjects). H2O2 was used to stimulate the human macrophage line U937 to mimic the oxidative stress status in severe asthma. The ability of compounds including PI3K inhibitors (BEZ235 and LY294002) to ameliorate GC insensitivity in severe asthma was evaluated.Results: PBMCs from patients with severe asthma exhibited dose-dependent and time-dependent GC insensitivity, which correlated with reduced activity of histone deacetylase 2 (HDAC2) and elevated expression of proinflammatory genes (nuclear factor-κB (NF-κB) and activator protein-1 (AP-1)) compared with these parameters in the control group. The PI3K inhibitors (BZE235 and LY294002) significantly restored the GC sensitivity of PBMCs from patients with severe asthma. In vitro, the PI3K inhibitors (BZE235 and LY294002) ameliorated GC insensitivity in H2O2/TNFα-induced IL-8 release from U937 cells by independently restoring the activity of HDAC2 or inhibiting the activation of transcription factors.Conclusions: This study demonstrates that PI3K inhibitors ameliorate GC insensitivity in severe asthma by restoring HDAC2 activity and inhibiting the phosphorylation of nuclear signaling transcription factors.FootnotesCite this article as: European Respiratory Journal 2020; 56: Suppl. 64, 2906.This abstract was presented at the 2020 ERS International Congress, in session “Respiratory viruses in the "pre COVID-19" era”.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).