Name: Tirumalai Rangasamy
Department: Environmental Health Sciences
Mentor: Shyam Biswal
Title of Project: Nrf2 Determines The Susceptibility To Cigarette Smoke-Induced emphysema and Allergen-Induced Asthma In Mice
Abstract: Although oxidative stress has been postulated to play an important role in the pathogenesis of chronic obstructive pulmonary disease (emphysema + bronchitis) and asthma, this has been very difficult to demonstrate with certainty. Nrf2 is a redox-sensitive b-ZIP transcription factor that is involved in the transcriptional regulation of multiple antioxidant genes. Here we show that disruption of the Nrf2 gene led to earlier-onset and more extensive CS-induced emphysema and allergen-induced asthma than found in wild-type littermates. Emphysema in Nrf2-deficient mice exposed to CS for 6 months was associated with more pronounced bronchoalveolar inflammation; with enhanced alveolar expression of 8-oxo-dG, a marker of oxidative stress; and with an increased apoptosis of endothelial and type II epithelial cells as compared with wild-type mice. Enhanced asthmatic response in response to allergen challenge in Nrf2-disrupted mice was associated with more pronounced mucus cell hyperplasia, increased airway hyperresponsiveness and infiltration of eosinophils into the lungs.Nrf2-disruption resulted in an increased expression of the Th2 cytokines, IL-4 and IL-13 in bronchoalveolar lavage fluid following allergen-challenge. Oligonucleotide microarray and Real Time RT-PCR analysis identified the expression of nearly 50 Nrf2-dependent antioxidant and cytoprotective genes in the lung that may work in concert to counteract CS and allergen-induced oxidative stress and inflammation. Our studies suggest that the responsiveness of Nrf2-directed antioxidant pathways may act as a major determinant of susceptibility to tobacco smoke-induced emphysema and allergen-induced asthma by upregulating antioxidant defenses and decreasing lung inflammation and alveolar cell apoptosis.
