Enhancement of systemic and sputum granulocyte response to inhaled endotoxin in people with the GSTM1 null genotype: Figure 1

Abstract

Objective To determine if the GSTM1 null genotype is a risk factor for increased inflammatory response to inhaled endotoxin. Methods 35 volunteers who had undergone inhalation challenge with a 20 000 endotoxin unit dose of Clinical Center Reference Endotoxin (CCRE) were genotyped for the GSTM1 null polymorphism. Parameters of airway and systemic inflammation observed before and after challenge were compared in GSTM1 null (n=17) and GSTM1 (n=18) sufficient volunteers. Results GSTM1 null volunteers had significantly increased circulating white blood cells (WBCs), polymorphonuclear neutrophils (PMNs), platelets and sputum PMNs (% sputum PMNs and PMNs/mg sputum) after CCRE challenge. GSTM1 sufficient volunteers had significant, but lower increases in circulating WBCs, PMNs and % sputum PMNs, and no increase in platelets or PMNs/mg sputum. Linear regression analysis adjusted for baseline values of the entire cohort revealed that the GSTM1 null genotype significantly increased circulating WBCs, platelets and % sputum PMNs after challenge Conclusion These data support the hypothesis that the GSTM1 null genotype is a risk factor for increased acute respiratory and systemic inflammatory response to inhaled CCRE. These data are consistent with other observations that the GSTM1 null genotype is associated with increased respiratory, systemic and cardiovascular effects linked to ambient air particulate matter exposure and indicate that the GSTM1 null genotype should be considered a risk factor for adverse health effects associated with exposure to environmental endotoxin.

Asthmatic Airway Neutrophilia after Allergen Challenge Is Associated with the Glutathione S-Transferase M1 Genotype

“…This implies that the allergen sensitivity of the GSTM1 1 group is greater. The promoting role of GSTM1 on neutrophilic airway inflammation in our homogenous population of individuals with atopic asthma contradicts previous studies showing a protective role of the wild-type GSTM1 genotype on ozone-and endotoxininduced airway neutrophilia (17,43,44) or diesel exhaust particles-enhanced response of nasal mucosa to allergen (18). However, it is important to emphasize that asthmatic airway epithelial cells are intrinsically different from normal or nasal epithelial cells; thus, biochemical interactions involving GSTM1 could be incomparable in these anatomically comparable but functionally dissimilar cells (45,46).…”

Endotoxin and β-1,3- d -Glucan in Concentrated Ambient Particles Induce Rapid Increase in Blood Pressure in Controlled Human Exposures

“…4 Recent studies showed that endotoxin stimulated airway inflammatory responses including granulocyte recruitment in healthy volunteers. 8, 29-31 Endotoxin activates the generation of inflammatory cytokines in human vascular endothelial cells, indicating that endotoxin-induced inflammation plays an important role in pathogenesis of vasculitis and arteriosclerosis. 32 Acute inhalation of high-dose endotoxin can cause immune failure symptoms such as systemic vasodilation – leading to hypotension and diminished myocardial contractility, 10, 11 while chronic inhalation of lower doses is associated with airway inflammation and respiratory organs impairment.…”

Reproducibility of the inflammatory response to inhaled endotoxin in healthy volunteers

“…Reproducibility was also assessed when two challenges were conducted with either relatively short or prolonged time intervals between each challenge. We have also sought to confirm the observation that persons with the homozygous glutathione-S-transferase mu-1 (GSTM1) genotype have increased PMN responses to inhaled LPS (5). …”

“…We have previously reported that the GSTM1 genotype modifies airways neutrophil response to inhaled LPS (5) and ozone (3, 7), with GSTM1 null individuals having increased sputum neutrophils following both LPS and ozone. In this study, we observed that subjects with the GSTM1 null genotype were associated with increased IL-8 response to LPS.…”