The Glutathione-S-Transferase Mu 1 null genotype modulates ozone-induced airway inflammation in humans

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. Conclusion— The GSTM1 null genotype is associated with increased airways inflammation 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.