Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not fully reversible. It is a disabling condition associated with progressive breathlessness. COPD will account for over 6 million deaths per year in 2020 (3rd major cause of death), and move from the sixth- to the third-leading cause of death worldwide. In America, COPD affects 9% of residents aged 60 years and above and it ranked fourth in the recent morbidity survey of the elderly population. It is estimated that approximately 23.4 million people in the US have COPD and the health burden is $36.1 billions per year. At present, there is no effective treatment exists to halt the decline in lung function in response to smoking. This in turn reflects a lack of understanding of the specific cellular and molecular pathways triggered in the lung by tobacco smoke/oxidants.

Our laboratory is interested in understanding the redox signaling, mechanism of proinflammatory gene expression by studying the chromatin remodeling-epigenetic changes (histone acetylation/deacetylation) on pro-inflammatory genes, involvement of anti-inflammatory and anti-aging proteins sirtuins, and steroid resistance in chronic inflammatory diseases/COPD. Recent research includes in understanding the role of sirtuins in aging and accelerated decline in lung function and regulation of circadian genes. Our long-term goal is to understand the cellular and molecular mechanisms involved in pathogenesis of COPD, and the potential benefit of therapeutic interventions in this debilitating disease.

Research Project #1: Mechanisms of cigarette smoke-induced chromatin remodeling in lung inflammation. The goal of this proposal is to understand the cellular and molecular mechanisms of cigarette Smoke-mediated IKKα activation leading to chromatin remodeling in airway epithelial cells and in mouse lungs, and role of HDAC2 in steroid resistance in response to cigarette smoke which is having translational relevance to patients with COPD in terms of understanding the molecular mechanisms of abnormal lung inflammation.

Research Project #2: Role of sirtuin in regulation of cigarette smoke-induced lung inflammation and injury. The major goal of this proposal is to understand the role of Sirtuin1 (SIRT1) in lung premature lung aging (apoptosis/senescence), emphysema and inflammation in response to cigarette smoke and in patients with COPD. The proposal will identify key intracellular signaling events in the SIRT1 pathway and will allow us to identify therapeutic targets for cigarette smoke-mediated abnormal lung inflammation and airway injury in pathogenesis of COPD. These studies have high translaational potential as SIRT1 is implicated in control of aging, senescence and imflammation.

Research Project #3: Circadian-coupled cellular signaling in chronic inflammatory conditions The goals of this proposal is to elucidate the role of peripheral circadian periodicity genes/proteins-CLOCK, BMAL1 and Period2 in regulating lung cellular, molecular and physiological functions in pathogenesis of COPD, and deficiency or posttranslational modifications of circadian proteins lead to loss of efficacy of steroids and β2-agonists in patients with COPD and during its exacerbations, and strategic chronotherapeutic manipulation of circadian proteins which has translational potential to treat patients with COPD.

Recent Publications

Hwang JW, Rajendrasozhan S, Yao H, Chung S, Sundar IK, Kinnula VL, Rahman I. FoxO3 deficiency leads to increased susceptibility to cigarette smoke-induced inflammation, airspace enlargement, and chronic obstructive pulmonary disease. J Immunol. 2011; 187:987-998. PMID: 21690325

Yao H, Rahman I. Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease, and therapeutic targets. Toxicol Appl Pharmacol 2011; 254: 72-85. PMID: 21296096

Sundar IK, Mullapudi N, Yao H, Spivack SD, Rahman I. Lung cancer and its association with COPD: update on the nexus of COPD and lung cancer. Curr Opin Pul Med 2011; 17:279–285. PMID: 21537190

Sundar IK, Hwang JW, Wu S, Sun J, Rahman I. Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinases and lymphoid aggregates formation. Biochem Biophys Res Commun 2011; 406: 127-133. PMID: 21300024

Edirisinghe I, Rahman I. Cigarette smoke-mediated oxidative stress, shear stress, and endothelial dysfunction: role of VEGFR2. Ann N Y Acad Sci 2010; 1203: 66-72. PMID: 20716285

Chung S, Yao H, Caito S, Hwang JW, Arunachalam G, Rahman I. Regulation of SIRT1 in cellular functions: role of polyphenols. Arch Biochem Biophys 2010; 501: 79-90. PMID: 20450879

Adenuga D, Caito S, Yao H, Sundar IK, Hwang JW, Chung S, Rahman I. Nrf2 Deficiency influences susceptibility to steroid resistance via HDAC2 reduction. Biochem Biophys Res Commun 2010; 403:452-456. PMID: 21094147

Sundar IK, Chung S, Hwang JW, Arunachalam G, Cook S, Yao H, Mazur W, Kinnula VL, Fisher AB, Rahman I. Peroxiredoxin 6 differentially regulates acute and chronic cigarette smoke-mediated lung inflammatory response and injury. Exp Lung Res 2010; 36: 451-462. PMID: 20939758

Yao H, Arunachalam G, Hwang JW, Chung S, Sundar IK, Kinnula VL, Crapo JD, Rahman I. Extracellular superoxide dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ECM. Proc Natl Acad Sci USA 2010; 107: 15571-15576. PMID: 20713693

Arunachalam G, Sundar IK, Hwang JW, Yao H, Rahman I. Emphysema is associated with increased inflammation in lungs of atherosclerosis-prone mice by cigarette smoke: implications in comorbidities of COPD. J Inflamm (Lond) 2010; 7:34. PMID: 20663150

Hwang JW, Chung S, Sundar IK, Yao H, Arunachalam G, McBurney MW, Rahman I. Cigarette smoke-induced autophagy is regulated by SIRT1-PARP-1-dependent mechanism: implication in pathogenesis of COPD. Arch Biochem Biophys 2010; 500: 203-209. PMID: 20493163

Chung S, Sundar IK, Yao H, Ho YS, Rahman I. Glutaredoxin 1 regulates cigarette smoke-mediated lung inflammation through differential modulation of I{kappa}B kinases in mice: impact on histone acetylation. Am J Physiol Lung Cell Mol Physiol 2010; 299: L192-203. PMID: 20472709

Adenuga D, Rahman I. Protein kinase CK2-mediated phosphorylation of HDAC2 regulates co-repressor formation, deacetylase activity and acetylation of HDAC2 by cigarette smoke and aldehydes. Arch Biochem Biophys 2010; 498: 62-73. PMID: 20388487

Caito S, Rajendrasozhan S, Cook S, Chung S, Yao H, Friedman AE, Brookes PS, Rahman I. SIRT1 is a redox-sensitive deacetylase that is post-translationally modified by oxidants and carbonyl stress. FASEB J 2010; 24: 3145-59. PMID: 20385619

Arunachalam G, Yao H, Sundar IK, Caito S, Rahman I. SIRT1 regulates oxidant- and cigarette smoke-induced eNOS acetylation in endothelial cells: Role of resveratrol. Biochem Biophys Res Commun 2010; 393: 66-72. PMID: 20102704

Rajendrasozhan S, Hwang JW, Yao H, Kishore N, Rahman I. Anti-inflammatory effect of a selective IkappaB kinase-beta inhibitor in rat lung in response to LPS and cigarette smoke. Pulm Pharmacol Ther 2010; 23:172-81. PMID: 20080200

Caito S, Hwang JW, Chung S, Yao H, Sundar IK, Rahman I. PARP-1 inhibition does not restore oxidant-mediated reduction in SIRT1 activity. Biochem Biophys Res Commun 2010; 392:264-70. PMID: 20060806

Yao H, Hwang JW, Moscat J, Diaz-Meco MT, Leitges M, Kishore N, Li X, Rahman I. Protein kinase C zeta mediates cigarette smoke/aldehyde- and lipopolysaccharide-induced lung inflammation and histone modifications. J Biol Chem 2010; 285: 5405-16. PMID: 20007975

Rajendrasozhan S, Chung S, Sundar IK, Yao H, Rahman I. Targeted disruption of NF-{kappa}B1 (p50) augments cigarette smoke-induced lung inflammation and emphysema in mice: a critical role of p50 in chromatin remodeling. Am J Physiol Lung Cell Mol Physiol 2010; 298: L197-209. PMID: 19965984

Edirisinghe I, Arunachalam G, Wong C, Yao H, Rahman A, Phipps RP, Jin ZG, Rahman I. Cigarette-smoke-induced oxidative/nitrosative stress impairs VEGF- and fluid-shear-stress-mediated signaling in endothelial cells. Antioxid Redox Signal 2010; 12: 1355-69. PMID: 19929443