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The glutathione-S-transferase Mu 1 null genotype modulates ozone-induced airway inflammation in humans*
Citation:
ALEXIS, N., H. Zhou, J. C. LAY, B. Harris, M. L. Hernandez, T. Lu, P. A. BROMBERG, D. DIAZ-SANCHEZ, R. B. DEVLIN, S. R. KLEEBERGER, AND D. B. PEDEN. The glutathione-S-transferase Mu 1 null genotype modulates ozone-induced airway inflammation in humans*. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. Journal of Allergy Clinical Immunology, 124(6):1222-1228, (2009).
Impact/Purpose:
The purpose of this study was to determine if the GSTM1 null genotype modulates ozone responses in humans
Description:
Background: The Glutathione-S-Transferase Mu 1 null genotype has been reported to be a risk factor for acute respiratory disease associated with increases in ambient air ozone. Ozone is known to cause an immediate decrease in lung function and increased airway inflammation. However, it is not known if GSTM1 modulates these ozone responses in vivo in humans Objective: The purpose of this study was to determine if the GSTM1 null genotype modulates ozone responses in humans. Methods: Thirty-five normal volunteers were genotyped for the GSTM1 null mutation and underwent a standard ozone exposure protocol to determine if lung function and inflammatory responses to ozone were different between the 19 GSTM1 normal and 16 GSTM1 null volunteers. Results: GSTM1 did not modulate lung function responses to acute ozone. Granulocyte influx 4 hours after challenge was similar between GSTM1 normal and null volunteers. However, GSTM1 null volunteers had significantly increased airway neutrophils 24 hours after challenge, as well as increased expression of HLA-DR on airway macrophages and dendritic cells. 3 Conclusion: The GSTM1 null genotype is associated with increased airways inflammation 24 hours following ozone exposure, consistent with the lag time observed between increased ambient air ozone exposure and exacerbations of lung disease. Clinical Implications: These observations suggest that the GSTM1 null genotype likely confers increased risk for exacerbation of ozone-induced lung disease through promoting an enhanced neutrophilic and monocytic inflammatory response to ozone. Capsule summary: The GSTM1 null genotype is associated with increased risk for ozone-induced lung disease. We report the GSTM1 genotype modulates ozone-induced inflammation but not lung function, and may predict persons at risk for environmental lung disease. Key words. Glutathione-S-Transferase Mu 1, Ozone, Pollution, Inflammation, Polymorphonuclear Neutrophil, Macrophage, Dendritic cell Abbreviations. Glutathione-S-Transferase Mu 1 (GSTM1), Ozone (03) , NAD(P)H:quinone oxidoreductase (NQ01), Nuclear Factor-E2-related factor-2 (NRF2), Polymorphonuclear Neutrophil (PMN), Forced Vital Capacity (FVC), Forced expiratory Volume at one second (FEV1), Clara Cell Protein 16 (CC16), Dendritic Cell (DC), mean fluorescence intensity (MFI), Expiratory minute ventilation (VEmin), dithiothreitol (OTT); dendritic cell (DC). Mean Fluorescence Intensity (MFI). "Although the research described in this article has been funded wholly or in part by the United States Environmental Protection Agency through cooperative agreement CR-83346301 with the Center for Environmental Medicine and Lung Biology at the University of North Carolina at Chapel Hill, it has not been subjected to the Agency's required peer and policy review, and therefore does not necessarily reflect the views of the Agency and no official endorsement should be inferred."
