The glutathione-S-transferase Mu 1 null genotype modulates ozone-induced airway inflammation in human subjects

Abstract

Background: The glutathione-S-transferase Mu 1 (GSTM1) null genotype has been reported to be a risk factor for acute respiratory disease associated with increases in ambient air ozone levels. Ozone is known to cause an immediate decrease in lung function and increased airway inflammation. However, it is not known whether GSTM1 modulates these ozone responses in vivo in human subjects.

Objective: The purpose of this study was to determine whether the GSTM1 null genotype modulates ozone responses in human subjects.

Methods: Thirty-five healthy volunteers were genotyped for the GSTM1 null mutation and underwent a standard ozone exposure protocol to determine whether lung function and inflammatory responses to ozone were different between the 19 GSTM1 wild type 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 24 hours after ozone exposure, which is consistent with the lag time observed between increased ambient air ozone exposure and exacerbations of lung disease.

Figure 1. Effect of GSTM1 genotypes on lung function response to O₃

FEV1 (top panel) and FVC (bottom panel) expressed as mean (SEM) percent of baseline value 4 and 24 hours after O₃ exposure in GSTM1+ (N=19, closed bars) and GSTM1− (N=16, open bars ).

Figure 2. Effect of GSTM1 genotypes on PMN and macrophage numbers in sputum in response to O₃

Mean (SEM) PMNs/mg sputum (top panel) and macrophages/mg sputum (bottom panel) pre (baseline), 4 and 24 hours post O₃ exposure in GSTM1+ (N=19 closed bars) and GSTM1− (N=16 open bars) individuals. * p<0.05 vs. baseline; ⁺p<0.05 GSTM1+ vs GSTM1−

Figure 3. Effect of GSTM1 genotypes on cell function 24 hours after O₃ exposure

Mean (SEM) oxidative burst activity, MFI (top, macrophages, GSTM1+ =17, GSTM1− =16), phagocytosis (middle, macrophages, GSTM1+ =19, GSTM1− = 15) and HLA-DR expression, MFI (bottom, GSTM1+ = 9. GSTM1− = 11) at 4 and 24 hours following ozone exposure in GSTM1+ and GSTM1− individuals. * p<0.05 vs pre; ⁺ p<0.05 for 24 hour response in GSTM1+ vs GSTM1− individuals