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

Alexis, Neil E.; Zhou, Haibo; Lay, John C.; Harris, Bradford D.; Hernández, Michelle; Lu, Tsui Shan; Bromberg, Philip A.; Díaz-Sánchez, David; Devlin, Robert B.; Kleeberger, Steven R.; Peden, David B.

doi:10.1016/j.jaci.2009.07.036

Cited by 71 publications

(47 citation statements)

References 29 publications

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“…In addition to the epidemiological studies outlined in the introduction, GSTM1 null volunteers with asthma have increased nasal response to allergen after experimental diesel exhaust and tobacco smoke exposure,6 and we have shown that those with the GSTM1 null genotype have increased PMN influx to the airway 24 h following exposure to 0.4 ppm O 3. 9 In a cohort of volunteers who were exposed to 0.4 ppm O 3 and 20 000 EU CCRE on separate occasions, we found a strong within-individual correlation between O 3 and CCRE-evoked PMN response 12. Thus, susceptibility to O 3 also correlated with susceptibility to endotoxin (CCRE).…”

Section: Discussionmentioning

confidence: 70%

“…All volunteers had normal lung function, normal methacholine challenge and negative skin tests and were genotyped only after challenge and assessment of samples was completed, thus avoiding selection bias. Venipuncture, induced sputum, spirometry, cytokine measurements in sputum and genotyping for GSTM1 were performed as previously described 8 9. Circulating total WBCs, PMNs and platelet counts, sputum PMNs and mediators in recovered sputum samples, spirometry measures and symptom scores were assessed at baseline (pre-challenge) and 4 h after CCRE challenge was complete in GSTM1 null and sufficient cohorts.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2011

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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.

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Section: Discussionmentioning

confidence: 70%

Section: Methodsmentioning

confidence: 99%

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

et al. 2011

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“…Subjects with the GSTMI null genotype have increased neutrophil influx to the airway 24 hours following exposure to ozone at a level of 400 ppb [51]. A study by Wu et.…”

Section: Oxidative Stress Genes and Susceptibility To Air Pollutionmentioning

confidence: 99%

The effect of environmental oxidative stress on airway inflammation

Auerbach

Hernández

2012

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of review Asthma is an inflammatory respiratory condition with significant associated morbidity and mortality that is increasing in prevalence. Air pollution is an important factor in both the development of asthma and in asthma exacerbations. Oxidative stress as a result of exposure to air pollution and underlying genetic polymorphisms that may play a role in susceptibility to this oxidative stress are the subject of current investigation. This article reviews the data regarding the effects of air pollution on the innate immune response and potential clinical and treatment implications of how genetic polymorphisms affect this response. Recent findings Recent investigation reveals how pollutant-induced oxidative stress impacts airway inflammatory responses. Work by our study group demonstrates that asthmatic patients have an exaggerated inflammatory response to air pollution induced oxidative stress. New trials investigating antioxidants as potential therapeutic interventions may target this specific issue. Summary Air pollution plays a critical role in asthma and may affect certain patients more than others. Further investigation into the genetic polymorphisms that affect inflammatory responses may help target patient populations at greatest risk for air pollution induced asthma and may provide new therapeutic options for these patient populations.

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“…Subjects inhaled LPS via a DeVilbiss Ultraneb 99 ultrasonic nebulizer. Induced sputum was obtained 4 hours post-LPS inhalation and processed as previously described (20-23). Cell viability (trypan blue exclusion) and total cell counts were assessed in a Neubauer hemacytometer and differential cell counts were performed on cytocentrifuged cells stained with a modified Wright's stain, (Hema-Stain -3, Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers

Hernández¹,

Mills²,

Almond³

et al. 2015

Journal of Allergy and Clinical Immunology

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Background Asthma with neutrophil predominance is challenging to treat with corticosteroids. Novel treatment options for asthma include those that target innate immune activity. Recent literature has indicated a significant role for IL-1β in both acute and chronic neutrophilic asthma. Objective This study used inhaled endotoxin (LPS) challenge as a model of innate immune activation to a) assess the safety of the interleukin-1 receptor antagonist, anakinra, in conjunction with inhaled LPS and b) to test the hypothesis that IL-1 blockade will suppress acute neutrophil response to challenge with inhaled LPS. Methods In a phase I clinical study, 17 healthy volunteers completed a double-blinded, placebo controlled crossover study where they received 2 daily subcutaneous doses of 1 mg/kg anakinra (maximum dose of 100 mg) or saline (placebo). One hour after the second treatment dose, subjects underwent an inhaled LPS challenge. Induced sputum was assessed for neutrophils 4 hours after inhaled LPS. The effect of anakinra compared to placebo on airway neutrophils and airway pro-inflammatory cytokines after LPS challenge was compared using a linear mixed model approach. Results Anakinra pretreatment significantly diminished airway neutrophilia compared to placebo. LPS-induced IL-1β, IL-6, and IL-8 were significantly reduced during the anakinra treatment period compared to placebo. Subjects tolerated the anakinra treatment well, without increased frequency of infections that were attributable to anakinra treatment. Conclusions Anakinra effectively reduced airway neutrophilic inflammation and resulted in no serious adverse events in a model of inhaled LPS challenge. Anakinra is a potential therapeutic candidate for treatment of asthma with neutrophil predominance in diseased populations.

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

Cited by 71 publications

References 29 publications

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

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

The effect of environmental oxidative stress on airway inflammation

IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers

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