6533b7d4fe1ef96bd1261c3e

RESEARCH PRODUCT

LATE-BREAKING ABSTRACT: Anti-inflammatory effect of RP6557, a dual PI3K δ/γ inhibitor, in glucocorticoid insensitive human neutrophils from chronic obstructive pulmonary disease patients

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Rationale: Glucocorticoid function is markedly impaired in patients with chronic obstructive pulmonary disease (COPD). Class I PI3K enzymes play a key role in chronic lung inflammation of COPD patients. This study explored differential inhibitory effects of dexamethasone and RP6557, a dual PI3K δ/γ inhibitor, on inflammatory responses in human neutrophils from healthy and COPD patients. Methods: Peripheral blood neutrophils were isolated from COPD patients andhealthy subjects and pre-incubated with dexamethasone (DEX) or RP6557 for 1 h. Neutrophils were stimulated with 5% cigarette smoke extract (CSE) for 6 h. Supernatants were used to measure IL-8 while RNA from neutrophils was analyzed for MKP1 and PI3Kγ expression levels. Results: Efficacy of DEX in attenuating CSE-induced IL-8 secretion was significantly reduced in COPD neutrophils compared to cells derived from healthy subjects (maximal % inhibition = 19.84 ± 11.46 vs. 83.9 ± 10.7) In contrast, RP6557 dose-dependently inhibited CSE-induced IL-8 secretion in cells from both COPD patients as well as healthy subjects (maximal % inhibition = 85.14 ± 8.24 Vs. 97.4 ± 5.3). Additionally, RP6557 reversed CSE-mediated changes in PI3Kγ ( p ) and MKP1 ( p ) expression. Conclusion: RP6557 demonstrated strong anti-inflammatory effect in inhibiting IL-8 secretion in neutrophils obtained from both healthy and COPD patients thereby indicating the therapeutic potential of this molecule in respiratory disorders. Additionally, RP6557 reversed CSE-induced PI3Kγ overexpression and MKP1 reduction which may explain its anti-inflammatory properties in COPD patients.