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Published ahead of print on January 3, 2008, doi:10.1164/rccm.200708-1269OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 8, April 2008, 861-870

A more recent version of this article appeared on April 15, 2008
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Submitted on August 29, 2007
Accepted on January 3, 2008

SIRT1, an Anti-Inflammatory and Anti-Aging Protein, is Decreased in Lungs of Patients with COPD

Saravanan Rajendrasozhan1, Se-Ran Yang1, Vuokko L Kinnula2, and Irfan Rahman1*

1 Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, New York, USA, 2 Department of Medicine (Pulmonary Division), University of Helsinki and Helsinki University Hospital, Helsinki, Finland

* To whom correspondence should be addressed. E-mail: irfan_rahman{at}urmc.rochester.edu.

Rationale: Abnormal inflammation and accelerated decline in lung function occur in patients with COPD. Human sirtuin (SIRT1), an anti-aging and anti-inflammatory protein, is a metabolic NAD+-dependent protein/histone deacetylase that regulates pro-inflammatory mediators by deacetylating histone and non-histone proteins. Objectives: To determine the expression of SIRT1 in lungs of smokers and in patients with COPD, and to elucidate the regulation of SIRT1 in response to cigarette smoke in macrophages, and its impact on NF-{kappa}B regulation. Methods: SIRT1 and NF-{kappa}B levels were assessed in lung samples of non-smokers, smokers and patients with COPD. Human monocyte-macrophage cells (MonoMac6) were treated with cigarette smoke extract (CSE) to determine the mechanism of CSE-mediated regulation of SIRT1 and its involvement in RelA/p65 regulation and IL-8 release. Results: Peripheral lungs of smokers and COPD patients showed decreased levels of nuclear SIRT1 as compared to non-smokers associated with its post-translational modifications (formation of nitrotyrosine and aldehyde carbonyl adducts). Treatment of MonoMac6 cells with CSE showed decreased levels of SIRT1 associated with increased acetylation of RelA/p65 NF-{kappa}B. Mutation or knock-down of SIRT1 resulted in increased acetylation of nuclear RelA/p65 and IL-8 release, whereas overexpression of SIRT1 decreased IL-8 release in response to CSE treatment in MonoMac6 cells. Conclusion: SIRT1 levels were reduced in macrophages and lungs of smokers and patients with COPD due to its post-translational modifications by cigarette smoke-derived reactive components leading to increased acetylation of RelA/p65. Thus, SIRT1 plays a pivotal role in regulation of NF-{kappa}B-dependent pro-inflammatory mediators in lungs of smokers and patients with COPD.
Key words: ROS; acetylation; NF-kB; inflammation; deacetylases




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