A role for phosphoinositol 3-kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease.
BACKGROUND
Glucocorticoid function is markedly impaired in the lungs of patients with chronic obstructive pulmonary disease (COPD). This reduction in glucocorticoid sensitivity might be due to an oxidant-mediated increase in phosphoinositol 3-kinase (PI3K) delta signaling.


OBJECTIVE
We sought to determine the role of PI3Kdelta in the reduced glucocorticoid responsiveness in patients with COPD.


METHODS
Peripheral lung tissue was obtained from 24 patients with COPD, 20 age-matched smokers with normal lung function, and 13 nonsmokers. Peripheral blood monocytes were isolated from 9 patients with COPD and 7 age-matched smokers with normal lung function and from healthy volunteers.


RESULTS
The expressions of PI3Kdelta and Akt phosphorylation were increased in macrophages from patients with COPD compared with those from control groups of age-matched smokers and nonsmokers. In vitro oxidative stress induced phosphorylation of Akt in monocytes and macrophages, which was abolished by means of selective inhibition of PI3Kdelta but not PI3Kgamma. Dexamethasone was less effective at repressing LPS-induced GM-CSF and CXC motif chemokine 8 release in blood monocytes from patients with COPD compared with age-matched smokers. This reduced sensitivity was reversed by inhibition of PI3Kdelta but not PI3Kgamma.


CONCLUSIONS
PI3Kdelta expression and signaling is increased in the lungs of patients with COPD. Selective inhibition of PI3Kdelta might restore glucocorticoid function in patients with COPD and might therefore present a potential therapeutic target.
Marwick
John A
JA
Centro di Ricerca su Asma e BPCO, Università di Ferrara, Ferrara, Italy. ohn.marwick@ed.ac.uk
Caramori
Gaetano
G
Casolari
Paolo
P
Mazzoni
Federico
F
Kirkham
Paul A
PA
Adcock
Ian M
IM
Chung
Kian Fan
KF
Papi
Alberto
A
D000368:Aged; D003907:Dexamethasone / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D012129:Respiratory Function Tests; D015398:Signal Transduction; D012907:Smoking / Q000276:immunology / Q000503:physiopathology; D016896:Treatment Outcome
D005938:Glucocorticoids; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases