Oxidative stress-induced corticosteroid insensitivity is reversed by formoterol via inhibition of PI3K signalling in peripheral blood mononuclear cells from patients with COPD and severe asthma

Rationale: COPD patients show a poor response to corticosteroids which has been linked to oxidative stress. Here we show that the long-acting β2-agonist formoterol (FM) reversed corticosteroid insensitivity after oxidative stress via inhibition of phosphoinositide-3-kinase (PI3K) signalling. Methods: The responsiveness to corticosteroids dexamethasone (DEX), budesonide (BUD) and fluticasone propionate (FP) was determined as IC50 on TNFα-induced IL-8 release in U937 monocytic cells or peripheral blood mononuclear cells (PBMCs) from patients with COPD or severe asthma. Results: PBMCs from patients with severe asthma and COPD are less sensitive to DEX compared to healthy volunteers. Although both FM (10-9M) and salmeterol (SM, 10-8M) reversed DEX insensitivity in PBMCs of severe asthma, only FM shows this effect in COPD. In U937 cells, exposure to H2O2 decreased BUD and FP sensitivity and increased Akt phosphorylation as a footprint of PI3K activation. FM restored sensitivity to BUD and FP while the effects of SM were weaker and not statistically significant, and FM but not SM, partially inhibited H2O2-induced Akt phosphorylation. H2O2 also decreased SM-induced cAMP production in U937 cells but did not affect the response to FM. The reduction of SM effects by H2O2 was reversed by pre-treatment with a PI3K inhibitor. Conclusion: These results suggest that FM restored corticosteroid sensitivity via inhibition of PI3K signalling and that a combination of a corticosteroid with FM may be more effective than that with SM in conditions of high oxidative stress, such as in COPD. Funded by AstraZeneca