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.

Cigarette smoke contains an enormous amount of toxic oxidants/free radicals molecules, the effects of which are deleterious to lung cells and also to induce inflammation, features that are hallmark of COPD. Other noxious environmental gases/particles such as NO2, SO2, and particulate matters (PM) can also cause oxidative stress and trigger inflammatory responses in the lungs in a susceptible population. Our major emphasis and focus has been on the question central to the disease - how does exposure to cigarette smoke cause inflammation in lungs and what determines some smokers develop more chronic inflammation associated with the development of COPD and/or lung cancer while some do not?

Glutathione is a ubiquitous, redox recycling, major thiol antioxidant molecule crucial for detoxification and scavenging of toxic oxidant molecules present in cigarette smoke. We have found that glutathione is pathologically depleted in lungs of smokers and COPD patients. Triggering the biosynthesis of this molecule in the lungs by pharmacological manipulation would help to avoid the damage and inflammation caused by cigarette smoke. Furthermore, it is known that glucocorticoids, which are very effective therapy for asthmatics, have failed to be beneficial to the COPD patients. Work from our laboratory has shown that the redox sensitive transcription factor NF-kB and the nuclear protein histone deacetylase (HDAC) central for glucocorticoid action are altered in response to cigarette smoking and oxidative stress. We hypothesized that these alterations lead to sustained and chronic inflammatory response by upregulation of pro-inflammatory genes. Inhibition of NF-kB signaling and modulation and induction of HDAC protein in the lung cells may therefore enable glucocorticoid therapy combat this progressively debilitating disease. Our research is directed to understand the cigarette smoke/oxidant-mediated NF-kB signaling and ways to induce HDAC protein as well as to increase the antioxidant glutathione screen by modulating its biosynthesis in the lungs. Our overall objective is to resolve the oxidative stress and inflammation in smokers and patients with COPD. We are also working on therapeutic interventions using small molecular weight compounds with dual antioxidant and anti-inflammatory actions to prevent or ameliorate the inflammation and enhance the efficacy of glucorticoids in COPD.

Our laboratory is also devoted to clinical translational research to study the biomarkers in induced sputum, breath condensate, plasma and urine to monitor COPD phenotype and progression, and to test pharmacological agents to control the progression of the disease in a large cohort of patients. We have developed a wide range of models (in vitro cell culture systems, ex-vivo human lungs and animal smoking models) to test the above hypothesis in response to cigarette smoke/oxidative stress. We currently use a wide variety of biochemical, cell and molecular biological tools to understand the various aspects of COPD biochemistry and molecular mechanisms underpinning the disease. We are actively collaborating with several research groups and pharmaceutical industries involved in environmental medicine/lung biology disease program to achieve our goals.

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Recent Publications

Yao H, Edirisinghe I, Yang SR, Rajendrasozhan S, Kode A, Caito S, Adenuga D, Rahman I. Genetic ablation of NADPH oxidase enhances susceptibility to cigarette smoke-induced lung inflammation and emphysema in mice. Am J Pathol. 2008 May;172(5):1222-1237

Yao H, Edirisinghe I, Rajendrasozhan S, Yang SR, Caito S, Adenuga D, Rahman I. Cigarette smoke-mediated inflammatory and oxidative responses are strain-dependent in mice. Am J Physiol Lung Cell Mol Physiol. 2008 Jun;294(6):L1174-1186.

Edirisinghe I, Yang SR, Yao H, Rajendrasozhan S, Caito S, Adenuga D, Wong C, Rahman A, Phipps RP, Jin ZG, Rahman I. VEGFR-2 inhibition augments cigarette smoke-induced oxidative stress and inflammatory responses leading to endothelial dysfunction. FASEB J. 2008 Jul;22(7):2297-2310.

Yao H, Yang SR, Edirisinghe I, Rajendrasozhan S, Caito S, Adenuga D, O’Reilly MA, Rahman I. Disruption of p21 attenuates lung inflammation induced by cigarette smoke, LPS, and fMLP in mice. Am J Respir Cell Mol Biol. 2008 Jul;39(1):7-18.

Yang SR, Valvo S, Yao H, Kode A, Rajendrasozhan S, Edirisinghe I, Caito S, Adenuga D, Henry R, Fromm G, Maggirwar S, Li JD, Bulger M, Rahman I. IKK alpha causes chromatin modification on pro-inflammatory genes by cigarette smoke in mouse lung. Am J Respir Cell Mol Biol. 2008 Jun;38(6):689-698.

Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. 2008. SIRT1, an Anti-Inflammatory and Anti-Aging Protein, is Decreased in Lungs of Patients with COPD. Am J Respir Crit Care Med. Apr 15;177(8):861-870.

Kode A, Rajendrasozhan S, Caito S, Yang SR, Megson IL, Rahman I. 2007. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am J Physiol Lung Cell Mol Physiol. Mar;294(3):L478-488.

Rahman I, Kode A, Biswas SK. 2006. Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nature Protocols, 1: 3159-3165.

Kode A, Yang SR, Rahman I. 2006. Differential effects of cigarette smoke on oxidative stress pro-inflammatory cytokine release in human primary airway epithelial cells and in a variety of transformed alveolar epithelial cells. Respir Res. 7: 132-152.

Yang SR, Wright J, Bauter M, Seweryniak K, Kode A, Rahman I. 2006. Sirtuin regulates cigarette smoke induced pro-inflammatory mediators release via acetylation of RelA/p65 NF-κB in macrophages in vitro and in vivo in rat lungs: implications for chronic inflammation and aging. Am J Physiol Lung Cell Mol Physiol. 292: 567-576.

Rahman I and Kilty I. 2006. Antioxidant Therapeutic Targets in COPD. Current Drug Targets, 7:707-720.

Rahman I, Yang S, Biswas S. 2006. Current concepts of redox signaling in the lungs. Antioxidant & Redox Signaling 8: 681-689.

Rahman I, Biswas SK, Kirkham PA. 2006. Regulation of inflammation and redox signaling by dietary polyphenols. Biochem Pharmacol. Nov 30;72(11):1439-1452. Review.

Biswas S, Chida AS, Rahman I. 2006. Redox modifications of protein-thiols: emerging roles in cell signaling. Biochem Pharmacol. 71: 551-64.

Rahman I, Biswas SK, Kode A. 2006. Oxidant and antioxidant balance in the airways and airway diseases. Eur J Pharmacol. Mar 8;533(1-3):222-239.

Yang SR, Chida AS, Bauter M, Shafiq N, Seweryniak K, Maggirwar SB, Kilty I, Rahman I. 2006. Cigarette smoke induces pro-inflammatory cytokine release by activation of NF-κB and post-translational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol. 291:L46-57.

Kirkham P, Rahman I. 2006. Oxidative stress in asthma and COPD: Antioxidants as a therapeutic strategy. Pharmacol Ther. 111: 476-494.