Tirumalai Rangasamy, Ph.D.

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.

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