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Published ahead of print on January 22, 2009, doi:10.1164/rccm.200810-1570OC
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American Journal of Respiratory and Critical Care Medicine Vol 179. pp. 542-548, (2009)
© 2009 American Thoracic Society
doi: 10.1164/rccm.200810-1570OC

Original Article

Inhibition of PI3K{delta} Restores Glucocorticoid Function in Smoking-induced Airway Inflammation in Mice

John A. Marwick1,2,3, Gaetano Caramori3, Christopher S. Stevenson2, Paolo Casolari3, Elen Jazrawi1, Peter J. Barnes1, Kazuhiro Ito1, Ian M. Adcock1, Paul A. Kirkham1,2 and Alberto Papi2

1 Airways Disease Section, National Heart & Lung Institute, Imperial College London, United Kingdom; 2 Novartis Institute for Biomedical Research, Respiratory Disease Area, Horsham, United Kingdom; and 3 Centro di Ricerca su Asma e BPCO, Università di Ferrara, Ferrara, Italy

Correspondence and requests for reprints should be addressed to Dr. John Marwick, Ph.D., National Heart & Lung Institute, Airways Disease Section, Imperial College London, Dovehouse Street, London SW3 6LY, UK. E-mail: j.marwick{at}imperial.ac.uk

Rationale: There is an increasing prevalence of reduced responsiveness to glucocorticoid therapy in severe asthma and chronic obstructive pulmonary disease (COPD). The molecular mechanism of this remains unknown. Recent studies have shown that histone deacetylase activity, which is critical to glucocorticoid function, is altered by oxidant stress and may be involved in the development of glucocorticoid insensitivity.

Objectives: To determine the role of phosphoinositol-3-kinase (PI3K) in the development of cigarette smoke–induced glucocorticoid insensitivity.

Methods: Wild-type, PI3K{gamma} knock-out and PI3K{delta} kinase dead knock-in transgenic mice were used in a model of cigarette smoke–induced glucocorticoid insensitivity. Peripheral lung tissue was obtained from six healthy nonsmokers, nine smokers with normal lung function, and eight patients with COPD.

Measurements and Main Results: In vitro oxidative stress activates PI3K and induced a relative glucocorticoid resistance, which is restored by PI3K inhibition. In vivo, cigarette smoke exposure in mice increased tyrosine nitration of histone deacetylase 2 in the lung, correlating with reduced histone deacetylase 2 activity and reduced glucocorticoid function. Histone deacetylase 2 activity and the antiinflammatory effects of glucocorticoids were restored in PI3K{delta} kinase dead knock-in but not PI3K{gamma} knock-out smoke-exposed mice compared with wild type mice, correlating with reduced histone deacetylase 2 tyrosine nitration. Glucocorticoid receptor expression was significantly reduced in smoke-exposed mice, in smokers with normal lung function, and in patients with COPD.

Conclusions: These data show that therapeutic inhibition of PI3K{delta} may restore glucocorticoid function in oxidative stress–induced glucocorticoid insensitivity.

Key Words: inflammation • histone deacetylase • chromatin • oxidative stress


AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject
Glucocorticoid unresponsiveness in severe asthma chronic obstructive pulmonary disease may involve an oxidant-mediated impairment of glucocorticoid receptor alpha function through reduction of histone deacetylase activity and co-repressor expression.

What This Study Adds to the Field
Histone deacetylase 2 activity is reduced in smoke-exposed mouse lungs, correlating with reduced glucocorticoid function, which is restored by PI3K{gamma} but not PI3K{delta} inhibition. GR{alpha} expression is reduced in smoke-exposed mouse lungs and in the lungs of patients with chronic obstructive pulmonary disease.

 



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