Oxidants/Antioxidants Imbalance in Chronic Obstructive Pulmonary Disease (COPD) and Allergic Asthma.

Our research interests relate to the balance between oxidants and antioxidants in obstructive lung diseases. Both COPD and asthma afflict more than one billion people in the world and 15-20% US population. Even though oxidative stress is suspected to be involved in the pathogenesis of asthma and COPD, it has been difficult to define relevant mechanistic pathways due to lack of good animal models. We study a mice deficient in the transcription factor Nuclear erythroid 2 p45 related factor 2 (Nrf2) to specifically dissect out the role of oxidative stress/antioxidants in the pathogenesis of COPD and asthma.Nrf2 is a CNC family of basic leuzine zipper transcription factor which regulates the transcriptional induction of almost all antioxidant and phase II detoxification genes in the lungs. Using gene expression profiling, molecular, immunological, and computer assisted topometric techniques, we found that Nrf2 is a major determinant of susceptibility to COPD and asthma. Disruption of the transcription factor Nrf2 in an emphysema resistant ICR mice strain led to early onset and more severe cigarette smoke-induced pulmonary emphysema [Rangasamy et. al. (2004) J.Clin.Invest. 114(9):1248-59] and asthma [Rangasamy et.al. (2005) J Exp Med. 202(1):47-59] after allergen challenge.


Pulmonary emphysema is one of the major pathological abnormalities associated with COPD. The damage to the lung in pulmonary emphysema is irreversible and available treatments for moderate disease, such as inhaled bronchodilators, provide only limited symptomatic relief. Hence, there is a strong need for new approaches that are capable of halting disease progression and interventions that repair/regenerate alveolar structures are desperately needed. A number of animal and human studies have revealed that tissue-specific stem cells and bone-marrow derived mesenchymal stem cells (MSCs) contribute to lung tissue regeneration and protection and thus administration of exogenous stem/progenitor cells or humoral factors that can activate endogenous stem/progenitor cells may be a potent next-generation therapy for COPD. Mesenchymal stem cells (MSCs) are prime candidates for the repair and regeneration of damaged tissues and organs. Our discovery of Nrf2 as a novel factor for regulating emphysema and other critical lung diseases suggests that it may be possible to target Nrf2 to transcriptionally induce a broad spectrum of antioxidant and cytoprotective pathways. Currently we are investigating the efficacy of Nrf2 overexpressing (using lentivirus) mesenchymal stem cells in regenerating alveolar structures in cigarette-smoke induced pulmonary.

In allergic asthma studies, we are currently exploring the role of oxidative stress sensitive cell cycle inhibitor P21 Cip1 in the activation and maturation of lung dendritic cells and in the proliferation and differentiation T helper cell subsets (effector Th2 cells, memory T cells and T regulatory cells). These studies are conducted in collaboration with Dr. Steve N. Georas and Dr. Michael O'Reilly.

We are also using an automated cigarette smoke machine, imaging and computer assisted topometric techniques to investigate the role of negative regulator (ATF3) of Nrf2 in the pathogenesis of pulmonary emphysema in mice models. Inducible transgenic systems, gene knock-out mice, genomics, and standard molecular biology, biochemical, and immunological techniques are used in the laboratory.

• Emo J, Meednu N, Chapman TJ, Rezaee F, Balys M, Randall T, Rangasamy T, Georas SN. Lpa2 is a negative regulator of both dendritic cell activation and murine models of allergic lung inflammation. J Immunol. 2012 Apr 15; 188(8):3784-90.
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• Rangasamy T, Semenza GL, Georas SN. What is hypoxia-inducible factor-1 doing in the allergic lung? Allergy. 2011 Jul; 66(7):815-7.
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• Yoshida T, Mett I, Bhunia AK, Bowman J, Perez M, Zhang L, Gandjeva A, Zhen L, Chukwueke U, Mao T, Richter A, Brown E, Ashush H, Notkin N, Gelfand A, Thimmulappa RK, Rangasamy T, Sussan T, Cosgrove G, Mouded M, Shapiro SD, Petrache I, Biswal S, Feinstein E, Tuder RM. Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema. Nat Med. 2010 Jul; 16(7):767-73.
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• Rangasamy T, Williams MA, Bauer S, Trush MA, Emo J, Georas SN, Biswal S. Nuclear erythroid 2 p45-related factor 2 inhibits the maturation of murine dendritic cells by ragweed extract. Am J Respir Cell Mol Biol. 2010 Sep; 43(3):276-85.
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• Roman J, Rangasamy T, Guo J, Sugunan S, Meednu N, Packirisamy G, Shimoda LA, Golding A, Semenza G, Georas SN. T-cell activation under hypoxic conditions enhances IFN-gamma secretion. Am J Respir Cell Mol Biol. 2010 Jan; 42(1):123-8.
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• An SS, Kim J, Ahn K, Trepat X, Drake KJ, Kumar S, Ling G, Purington C, Rangasamy T, Kensler TW, Mitzner W, Fredberg JJ, Biswal S. Cell stiffness, contractile stress and the role of extracellular matrix. Biochem Biophys Res Commun. 2009 May 15; 382(4):697-703.
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• Rangasamy T, Misra V, Zhen L, Tankersley CG, Tuder RM, Biswal S. Cigarette smoke-induced emphysema in A/J mice is associated with pulmonary oxidative stress, apoptosis of lung cells, and global alterations in gene expression. Am J Physiol Lung Cell Mol Physiol. 2009 Jun; 296(6):L888-900.
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• Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, Bedja D, Yates MS, Kombairaju P, Yamamoto M, Liby KT, Sporn MB, Gabrielson KL, Champion HC, Tuder RM, Kensler TW, Biswal S. Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci U S A. 2009 Jan 6; 106(1):250-5.
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• Williams MA, Rangasamy T, Bauer SM, Killedar S, Karp M, Kensler TW, Yamamoto M, Breysse P, Biswal S, Georas SN. Disruption of the transcription factor Nrf2 promotes pro-oxidative dendritic cells that stimulate Th2-like immunoresponsiveness upon activation by ambient particulate matter. J Immunol. 2008 Oct 1; 181(7):4545-59.
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• Thimmulappa RK, Rangasamy T, Alam J, Biswal S. Dibenzoylmethane activates Nrf2-dependent detoxification pathway and inhibits benzo(a)pyrene induced DNA adducts in lungs. Med Chem. 2008 Sep; 4(5):473-81.
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• McGrath-Morrow S, Rangasamy T, Cho C, Sussan T, Neptune E, Wise R, Tuder RM, Biswal S. Impaired lung homeostasis in neonatal mice exposed to cigarette smoke. Am J Respir Cell Mol Biol. 2008 Apr; 38(4):393-400.
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• Singh A, Rangasamy T, Thimmulappa RK, Lee H, Osburn WO, Brigelius-Flohé R, Kensler TW, Yamamoto M, Biswal S. Glutathione peroxidase 2, the major cigarette smoke-inducible isoform of GPX in lungs, is regulated by Nrf2. Am J Respir Cell Mol Biol. 2006 Dec; 35(6):639-50.
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• Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, Biswal S. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest. 2006 Apr; 116(4):984-95.
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• Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med. 2005 Jul 4; 202(1):47-59.
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• Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, Biswal S. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest. 2004 Nov; 114(9):1248-59.
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• Biswal S, Maxwell T, Rangasamy T, Kehrer JP. Modulation of benzo[a]pyrene-induced p53 DNA activity by acrolein. Carcinogenesis. 2003 Aug; 24(8):1401-6.
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