Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of chronic morbidity and mortality in the United States, affecting an estimated 23 million people. COPD (emphysema and chronic bronchitis) is linked with premature aging (accelerated decline in lung function) and chronic inflammation of the lungs due to inhaled cigarette smoke-derived oxidants and free radicals which are implicated in aging, senescence, cancer and inflammatory processes. However, very little is known about the molecular mechanisms whereby cigarette smoke (CS) triggers abnormal and sustained lung inflammation and injury. The NAD+dependent protein deacetylases (sirtuins) have recently emerged as important regulators of aging (apoptosis/senescence), chronic inflammatory diseases and cancer. The founding member yeast Sir2 (ySir2, yeast silent information regulator 2) which is equivalent to human sirtuin1 (SIRT1) is essential for maintaining silent chromatin via the deacetylation of histones and non-histone proteins. We have found that SIRT1 levels are drastically reduced in response to CS exposure in macrophages, mouse lung, and in lungs of patients with COPD, and are associated with increased NF-(B activation and release of pro-inflammatory mediators. Similarly, SIRT1-deficient mice exhibited exaggerated levels of NF-(B and proinflammatory cytokines associated with increased influx of neutrophils, whereas these responses were attenuated in lungs of SIRT1 transgenic mice exposed to CS. Our preliminary data also show that SIRT1-/- mice are more prone to develop emphysema in response to CS exposure. We hypothesize that SIRT1 is a novel down-regulator of CS-induced lung inflammation and injury (emphysema) due to its effects on NF-(B, histone acetylation and apoptosis/cell senescence. We propose to test this hypothesis in vitro in monocytes/macrophages (the main orchestrators and amplifiers of the lung inflammatory response) and in vivo in mouse lungs exposed to CS. We propose to:
Aim 1 : determine the mechanisms by which CS exposure results in reduction of SIRT1 in macrophages and in mouse lungs;
Aim 2 : determine the mechanisms whereby SIRT1 regulates the inflammatory response to CS in macrophages and in mouse lungs;
and Aim 3 : determine the effects of genetic loss and gain of SIRT1 on CS-mediated lung inflammation/injury and airspace enlargement (emphysema) in vivo, and the mechanisms involved. These studies are designed to identify the regulatory mechanism of SIRT1 that is altered by CS leading to abnormal lung inflammation, and to determine the role of SIRT1 in CS-induced acetylation of histone proteins, apoptosis/senescence and airspace enlargement. The experiments outlined in this proposal will also identify key intracellular signaling events in the SIRT1 pathway and will allow us to identify therapeutic targets for CS-mediated abnormal lung inflammation and airway injury in pathogenesis of COPD. These studies have high translational potential as SIRT1 is implicated in control of aging, senescence and inflammation.
COPD is the fourth leading cause of chronic morbidity and mortality in the United States;hence it is a major public health concern. COPD is linked with the premature aging of the lungs due to cigarette smoke-derived free radicals and inflammatory processes in the lung. Our research will identify the key intracellular molecular events in the sirtuin 1 (an anti-aging and anti-inflammatory protein) pathway which will allow us to identify therapeutic targets for COPD-emphysema and other chronic inflammatory diseases linked to smoking.
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|Lerner, Chad A; Sundar, Isaac K; Yao, Hongwei et al. (2015) Vapors produced by electronic cigarettes and e-juices with flavorings induce toxicity, oxidative stress, and inflammatory response in lung epithelial cells and in mouse lung. PLoS One 10:e0116732|
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|Sundar, Isaac K; Ahmad, Tanveer; Yao, Hongwei et al. (2015) Influenza A virus-dependent remodeling of pulmonary clock function in a mouse model of COPD. Sci Rep 4:9927|
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|Hwang, Jae-Woong; Sundar, Isaac K; Yao, Hongwei et al. (2014) Circadian clock function is disrupted by environmental tobacco/cigarette smoke, leading to lung inflammation and injury via a SIRT1-BMAL1 pathway. FASEB J 28:176-94|
|Yao, Hongwei; Sundar, Isaac K; Ahmad, Tanveer et al. (2014) SIRT1 protects against cigarette smoke-induced lung oxidative stress via a FOXO3-dependent mechanism. Am J Physiol Lung Cell Mol Physiol 306:L816-28|
|Sundar, Isaac K; Yao, Hongwei; Huang, Yadi et al. (2014) Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD: implication for COPD-associated neuropathogenesis. PLoS One 9:e87999|
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