A role for PI 3 Kδ in the impairment of glucocorticoid responsiveness in COPD

26 Background: Glucocorticoid function is markedly impaired in the lungs of patients with 27 chronic obstructive pulmonary disease. This reduction in glucocorticoid sensitivity may be 28 due to an oxidant-mediated elevation in phosphoinositol 3-kinase  signaling. 29 Objective: To determine the role of phosphoinositol 3-kinase  in the reduced glucocorticoid 30 responsiveness in chronic obstructive pulmonary disease. 31 Methods: Peripheral lung was obtained from 24 patients with chronic obstructive pulmonary 32 disease, 20 age-matched smokers with normal lung function and 13 non-smokers. Peripheral 33 blood monocytes were isolated from 9 chronic obstructive pulmonary disease patients and 7 34 age-matched smokers with normal lung function and from healthy volunteers. 35 Results: The expression of phosphoinositol 3-kinase  and Akt phosphorylation were elevated 36 in macrophages from patients with chronic obstructive pulmonary disease patients as 37 compared to control groups of age-matched smokers and non-smokers. In vitro, oxidative 38 stress induced phosphorylation of Akt in monocytes and macrophages which was abolished 39 in by selective inhibition of phosphoinositol 3-kinase , but not phosphoinositol 3-kinase . 40 Dexamethasone was less effective at repressing lipopolysaccharide-induced granulocyte41 macrophage colony stimulating factor and CXC motif chemokine 8 release in blood 42 monocytes from chronic obstructive pulmonary disease patients as compared to age-matched 43 smokers. This reduced sensitivity was reversed by inhibition of phosphoinositol 3-kinase  44 but not phosphoinositol 3-kinase . 45 Conclusion: Phosphoinositol 3-kinase  expression and signaling is increased in the lungs of 46 chronic obstructive pulmonary disease patients. Selective inhibition of phosphoinositol 347 kinase δ may restore glucocorticoid function in chronic obstructive pulmonary disease 48 patients and may therefore present a potential therapeutic target. 49 50