Mechanisms of allergy and clinical immunologyA role for phosphoinositol 3–kinase δ in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease
Section snippets
Human study subjects
All subjects were recruited from the Section of Respiratory Medicine of the University Hospital of Ferrara, Italy. Peripheral lung tissue was collected from 24 patients with COPD, 20 smokers, and 13 nonsmokers (Table I). All subjects were undergoing elective surgery for lung cancer, and COPD was diagnosed retrospectively; these subjects were not taking bronchodilator, theophylline, antibiotic, antioxidant, and/or glucocorticoid therapy in the last month before surgery. Peripheral venous blood
PI3Kδ expression and phosphorylation of Akt (ser473) are increased in macrophages in the lungs of patients with COPD
Lung macrophages from patients with COPD are less responsive to glucocorticoid suppression of proinflammatory genes.12 Mice exposed to oxidative stress, such as cigarette smoke, are also relatively glucocorticoid insensitive, an effect that is prevented by the selective abolition of PI3Kδ, but not PI3Kγ, signaling.8 An increase in PI3Kδ activation might therefore represent a mechanism of glucocorticoid insensitivity in patients with COPD. PI3Kδ staining in macrophages in the peripheral lungs of
Discussion
We demonstrated that PI3Kδ expression and Akt phosphorylation in peripheral lung macrophages from patients with COPD are increased compared with those from healthy smokers or control subjects. Furthermore, selective inhibition of PI3Kδ but not PI3Kγ restored glucocorticoid-mediated repression of proinflammatory mediator release from monocytes isolated from patients with COPD to levels seen in control subjects. These data are consistent with our recent demonstration that transgenic mice lacking
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J. A. M. was supported by a European Respiratory Society Long-Term Fellowship (number 87) and by a grant from the UK Medical Research Council (grant G0700900). Work in the author's laboratories is also supported by the Associazione per la Ricerca e la Cura dell'Asma (ARCA, Padova, Italy; G. C. and A. P.) and by the Wellcome Trust (I. M. A.).
Disclosure of potential conflict of interest: J. A. Marwick receives research support from the European Respiratory Society (Fellowship number 87) and the Medical Research Council (UK) (MRC grant support number 0700900). I. M. Adcock receives research support from the Wellcome Trust, the MRC, and the Royal Society, and has received travel grants from Boehringer Ingelheim. K. F. Chung serves on advisory boards for Merck, Boehringer Ingelheim, and Gilead and receives research support from the Medical Research Council, the Wellcome Trust UK, and GlaxoSmithKline. A. Papi receives research support from Chiesi Farmaceutici, AstraZeneca, and Boehringer Ingelheim. The rest of the authors have declared that they have no conflict of interest.