Oxidative stress has been implicated in the pathogenesis of many acute and chronic lung diseases including asthma and chronic obstructive pulmonary disease (COPD). The source of this stress can be either extrinsic/environmental or intrinsic originating from cellular processes. Oxygen derived free radicals and other reactive oxygen species (ROS) are normal byproducts of cellular metabolism, but are also produced at high levels during metabolism of environmental pollutant such as ozone (O3). Because of the potential of these molecules to react with and damage major components of the cell, including lipids, proteins and DNA, extensive and redundant mechanisms have evolved to regulate their levels. These include both antioxidant enzymes and non-enzymatic scavenger molecules. An imbalance resulting from either excess production of ROS or deficiencies in these antioxidant mechanisms results in oxidative stress. Oxidative stress can result in cell damage leading to activation of inflammatory pathways which can perpetuate the redox imbalance in the lungs. Defense mechanisms capable of detoxification and reduction of ROS and neutralizing the deleterious effects of oxidative stress are particularly important in the lung, because it is an important point of contact with environmental pollutants that can add significantly to the intrinsic ROS burden. Given the potential impact of alterations in the antioxidant capacity of the lung on risk for lung disease, it is not surprising that polymorphisms in genes that contribute to redox balance and encode enzymes that efficiently metabolize reactive oxygen species in the lung have been the focus of numerous genetic studies. The glutathione S transferase (GST) family includes enzymes whose ability to metabolize a wide range of oxidative stress substrates suggests they are likely to play an important role in maintaining cellular integrity. These enzymes, which conjugate hydrophobic and electrophilic compounds with reduced glutathione, can be grouped into eight different families, with the majority of genetic studies focused on polymorphisms in GSTP1, a member of the pi family and GSTM1 and GSTT1, members of the mu and theta families. Polymorphisms in these genes have been associated with increased response to O3, risk for asthma, and decline in lung function in COPD patients. However, not all studies have consistently observed these associations, and in some cases contradictory results have been reported, leading many to conclude that gene-gene and/or gene-environment interactions may confound elucidation of the contribution of these polymorphisms to disease risk. In this application we propose to address the role of the human polymorphisms in response to oxidative stress using a unique panel of mice expressing either the protective or disease associated GST alleles.

Public Health Relevance

The lungs are constantly exposed to oxidants both from environmental pollutants and from normal cellular metabolism. Genetic variation between individuals in the genes that encode enzymes and proteins critical in protecting the lung from damage caused by excessive levels of oxidants are believed to influence the pathogenesis of many lung diseases, including asthma and COPD. Consistent with this, a number of genetic studies suggest that polymorphisms in glutathione S-transferase (GST) may in part influence either the development or severity of lung disease. In this application, we propose experiments designed to determine whether the polymorphisms in GSTM1, GSTP1 and GSTT1 identified in these association studies, either alone or when inherited in combination, are sufficient to alter the response of the lung to oxidative stress, specifically stress associated with ozone and allergen exposure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Postow, Lisa
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Fay, Matthew J; Nguyen, My Trang; Snouwaert, John N et al. (2015) Xenobiotic Metabolism in Mice Lacking the UDP-Glucuronosyltransferase 2 Family. Drug Metab Dispos 43:1838-46