Chronic obstructive pulmonary disease (COPD) is the third leading cause of chronic morbidity and mortality, both in the United States (affecting an estimated 23 million people) and globally. Cigarette smoke (CS), the most important etiological risk factor for the development of COPD, has been shown to cause DNA damage and cellular senescence, leading to premature and accelerated lung aging. The molecular mechanisms that lead to DNA damage and cellular senescence, however, as well as their roles in the development of COPD/emphysema are not known. Our preliminary data show that histone deacetylase 2 (HDAC2) level is significantly decreased in lung epithelial cells, fibroblasts and lungs of mice exposed to CS. This reduction is associated with specific changes in histone H3 acetylation and methylation. Furthermore, mice deficient in HDAC2 exhibit augmented DNA damage, impaired DNA non-homologous end joining (NHEJ) repair, cellular senescence and inflammatory response in lungs in response to CS exposure. However, no information is available regarding the role of HDAC2 in DNA damage/repair, stress-induced premature senescence (SIPS), or senescence-associated secretory phenotype (SASP), particularly in response to CS exposure in the lung. We hypothesize that CS causes persistent DNA damage and impairs NHEJ via HDAC2-dependent chromatin modifications, thereby leading to SIPS and SASP, and to subsequent pulmonary emphysema. To test this hypothesis, we plan to pursue the following three Specific Aims. (1) To determine whether CS-mediated DNA damage and NHEJ impairment lead to SIPS and SASP via HDAC2 reduction. Here, we will test the hypothesis that NHEJ becomes less efficient and DNA damage is increased when HDAC2 is reduced in response to CS exposure, leading to lung cellular SIPS and SASP. (2) To determine HDAC2-dependent chromatin mechanisms that underlie CS-mediated DNA damage, SIPS and SASP. We will investigate the role of HDAC2-regulated specific histone H3 modifications (acetylation and methylation) in DNA damage and repair in the lung. (3) To determine the involvement of DNA damage-mediated SIPS and SASP via HDAC2 reduction in development of pulmonary emphysema. We hypothesize that HDAC2 reduction contributes to epigenomic instability and subsequent emphysema due to SIPS and SASP. The outcome of this proposal will not only unravel HDAC2-dependent epigenetic chromatin mechanisms underlying DNA damage-induced senescence, but also provide understanding of the role of SIPS and SASP in the development of COPD/emphysema. Overall, these studies will have translational potential to identify novel therapeutic targets in ameliorating premature lung aging in COPD.

Public Health Relevance

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of chronic morbidity and mortality in the United States, and thus represents a major public health concern. COPD is linked to premature and accelerated aging of the lungs due to cigarette smoking. Our research will unravel key mechanisms in lung irreversible cellular growth arrest and DNA damage which will allow us to identify therapeutic targets and to develop novel therapeutic strategies to prevent the premature aging of the lung in the development of COPD-emphysema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085613-06
Application #
8602851
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Punturieri, Antonello
Project Start
2006-07-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
$345,375
Indirect Cost
$120,375
Name
University of Rochester
Department
Public Health & Prev Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Lerner, Chad A; Lei, Wei; Sundar, Isaac K et al. (2016) Genetic Ablation of CXCR2 Protects against Cigarette Smoke-Induced Lung Inflammation and Injury. Front Pharmacol 7:391
Lerner, Chad A; Rutagarama, Pierrot; Ahmad, Tanveer et al. (2016) Electronic cigarette aerosols and copper nanoparticles induce mitochondrial stress and promote DNA fragmentation in lung fibroblasts. Biochem Biophys Res Commun 477:620-5
Lerner, Chad A; Sundar, Isaac K; Rahman, Irfan (2016) Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD. Int J Biochem Cell Biol 81:294-306
Lerner, Chad A; Sundar, Isaac K; Watson, Richard M et al. (2015) Environmental health hazards of e-cigarettes and their components: Oxidants and copper in e-cigarette aerosols. Environ Pollut 198:100-7
Ahmad, Tanveer; Sundar, Isaac K; Lerner, Chad A et al. (2015) Impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease. FASEB J 29:2912-29
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
Sundar, Isaac K; Nevid, Michael Z; Friedman, Alan E et al. (2014) Cigarette smoke induces distinct histone modifications in lung cells: implications for the pathogenesis of COPD and lung cancer. J Proteome Res 13:982-96
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
Yao, Hongwei; Sundar, Isaac K; Gorbunova, Vera et al. (2013) P21-PARP-1 pathway is involved in cigarette smoke-induced lung DNA damage and cellular senescence. PLoS One 8:e80007
Yao, Hongwei; Hwang, Jae-woong; Sundar, Isaac K et al. (2013) SIRT1 redresses the imbalance of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9 in the development of mouse emphysema and human COPD. Am J Physiol Lung Cell Mol Physiol 305:L615-24

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