Mechanisms of allergy and clinical immunology
A role for phosphoinositol 3–kinase δ in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease

https://doi.org/10.1016/j.jaci.2010.02.003Get rights and content

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) δ signaling.

Objective

We sought to determine the role of PI3Kδ 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 PI3Kδ 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 PI3Kδ but not PI3Kγ. 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 PI3Kδ but not PI3Kγ.

Conclusion

PI3Kδ expression and signaling is increased in the lungs of patients with COPD. Selective inhibition of PI3Kδ might restore glucocorticoid function in patients with COPD and might therefore present a potential therapeutic target.

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

References (36)

  • P.J. Barnes

    Immunology of asthma and chronic obstructive pulmonary disease

    Nat Rev Immunol

    (2008)
  • K. Ito et al.

    Update on glucocorticoid action and resistance

    J Allergy Clin Immunol

    (2008)
  • K. Ito et al.

    Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages

    FASEB J

    (2001)
  • J.A. Marwick et al.

    Inhibition of PI3Kδ restores glucocorticoid function in smoking-induced airway inflammation in mice

    Am J Respir Crit Care Med

    (2009)
  • J.A. Marwick et al.

    Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs

    Am J Respir Cell Mol Biol

    (2004)
  • K. Ito et al.

    Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-κB suppression

    J Exp Med

    (2006)
  • B. Cosio et al.

    Theophylline Restores histone deacetylase activity and steroid responses in COPD macrophages

    J Exp Med

    (2004)
  • K. Ito et al.

    Decreased histone deacetylase activity in chronic obstructive pulmonary disease

    N Engl J Med

    (2005)
  • Cited by (0)

    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.

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