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Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice.

Marwick, John and Caramori, Gaetano and Stevenson, Christopher and Casolari, Paolo and Jazrawi, Elen and Barnes, Peter J and Ito, Kazuhiro and Adcock, Ian M and Kirkham, Paul and Papi, Alberto (2009) Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice. American Journal of Respiratory and Critical Care Medicine, 179 (7). pp. 542-548. ISSN 1535-4970

Abstract

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, PI3Kgamma knock-out and PI3Kdelta 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 PI3Kdelta kinase dead knock-in but not PI3Kgamma 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 PI3Kdelta may restore glucocorticoid function in oxidative stress-induced glucocorticoid insensitivity.

Item Type: Article
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Additional Information: archiving status unclear?
Keywords: inflammation; histone deacetylase; chromatin; oxidative stress
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Date Deposited: 14 Dec 2009 13:48
Last Modified: 14 Dec 2009 13:48
URI: https://oak.novartis.com/id/eprint/1492

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