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SIRT1, an Antiinflammatory and Antiaging Protein, Is Decreased in Lungs of Patients with Chronic Obstructive Pulmonary Disease

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

Correspondence and requests for reprints should be addressed to Irfan Rahman, Ph.D., Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester, NY 14642. E-mail: irfan_rahman{at}urmc.rochester.edu

Rationale: Abnormal inflammation and accelerated decline in lung function occur in patients with chronic obstructive pulmonary disease (COPD). Human sirtuin (SIRT1), an antiaging and antiinflammatory protein, is a metabolic NAD⁺-dependent protein/histone deacetylase that regulates proinflammatory mediators by deacetylating histone and nonhistone proteins.

Objectives: To determine the expression of SIRT1 in lungs of smokers and patients with COPD, and to elucidate the regulation of SIRT1 in response to cigarette smoke in macrophages, and its impact on nuclear factor (NF)-B regulation.

Methods: SIRT1 and NF-B levels were assessed in lung samples of nonsmokers, 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.

Measurements and Main Results: Peripheral lungs of smokers and patients with COPD showed decreased levels of nuclear SIRT1, as compared with nonsmokers, 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-B. Mutation or knockdown 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.

Conclusions: 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-B–dependent proinflammatory mediators in lungs of smokers and patients with COPD.

Key Words: reactive oxygen species • acetylation • nuclear factor-B • inflammation • deacetylases

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Sirtuin (SIRT1) deacetylase is an antiaging and antiinflammatory protein. Cigarette smoke reduced SIRT1 levels by post-translational modifications, leading to acetylation of the RelA/p65 subunit of nuclear factor-B. What This Study Adds to the Field SIRT1 deacetylase is decreased in macrophages, and in lungs of smokers and patients with chronic obstructive pulmonary disease.

 

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