Anti-Oxidant N-Acetylcysteine Diminishes Diesel Exhaust-Induced Increased Airway Responsiveness in Person with Airway Hyper-Reactivity

Carlsten, Chris; MacNutt, Meaghan J.; Zhang, Zhihong; Sava, Francesco; Pui, Mandy

doi:10.1093/toxsci/kfu040

Cited by 53 publications

(51 citation statements)

References 34 publications

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“…We observed no significant effect of asthma status on our outcomes; this is likely due to being underpowered for an analysis focused specifically on asthma status, which was not the intention of our study. Accordingly, we neither expected nor observed any significant change in airway responsiveness given that the minority of our subjects had airway hyper-responsiveness at baseline, which we have already shown is the key predictor of a DE-attributable change 32. The focus on allergen-sensitised participants in our study allows demonstration that even in atopic non-asthmatics, inflammation may be induced in the lower airways without clinical symptoms of airway dysfunction.…”

Section: Discussioncontrasting

confidence: 53%

Diesel exhaust augments allergen-induced lower airway inflammation in allergic individuals: a controlled human exposure study

Carlsten

Blomberg

Pui

et al. 2015

Thorax

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101

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Rationale Traffic-related air pollution has been shown to augment allergy and airway disease. However, the enhancement of allergenic effects by diesel exhaust in particular is unproven in vivo in the human lung, and underlying details of this apparent synergy are poorly understood. Objective To test the hypothesis that a 2 h inhalation of diesel exhaust augments lower airway inflammation and immune cell activation following segmental allergen challenge in atopic subjects. Methods 18 blinded atopic volunteers were exposed to filtered air or 300 mg PM 2.5 /m 3 of diesel exhaust in random fashion. 1 h post-exposure, diluent-controlled segmental allergen challenge was performed; 2 days later, samples from the challenged segments were obtained by bronchoscopic lavage. Samples were analysed for markers and modifiers of allergic inflammation (eosinophils, Th2 cytokines) and adaptive immune cell activation. Mixed effects models with ordinal contrasts compared effects of single and combined exposures on these end points. Results Diesel exhaust augmented the allergen-induced increase in airway eosinophils, interleukin 5 (IL-5) and eosinophil cationic protein (ECP) and the GSTT1 null genotype was significantly associated with the augmented IL-5 response. Diesel exhaust alone also augmented markers of non-allergic inflammation and monocyte chemotactic protein (MCP)-1 and suppressed activity of macrophages and myeloid dendritic cells. Conclusion Inhalation of diesel exhaust at environmentally relevant concentrations augments allergen-induced allergic inflammation in the lower airways of atopic individuals and the GSTT1 genotype enhances this response. Allergic individuals are a susceptible population to the deleterious airway effects of diesel exhaust. Trial registration number NCT01792232.

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Section: Discussioncontrasting

confidence: 53%

Diesel exhaust augments allergen-induced lower airway inflammation in allergic individuals: a controlled human exposure study

Carlsten

Blomberg

Pui

et al. 2015

Thorax

Self Cite

101

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“…As expression of PP2A is known to be directly enhanced by mitochondrial reactive oxygen species (ROS), our analyses suggest that DE exacerbates the allergen-induced oxidative stress response. This is consistent with the findings of our previous studies linking inhaled DE-related airway responsiveness with variants in genes of oxidative stress metabolism [23,24]. This is also corroborated by our recent study demonstrating that DE particles activate transient receptor potential channels to initiate respiratory reflexes in a ROS-dependent mechanism [25].…”

Section: Discussionsupporting

confidence: 93%

Inhaled diesel exhaust alters the allergen-induced bronchial secretome in humans

et al. 2018

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Diesel exhaust (DE) is a paradigm for traffic-related air pollution. Human adaptation to DE is poorly understood and currently based on oversimplified models. DE promotes allergic responses, but protein expression changes mediated by this interaction have not been systematically investigated. The aim of this study was to define the effect of inhaled DE on allergen-induced proteins in the lung.We performed a randomised and blinded controlled human crossover exposure study. Participants inhaled filtered air or DE; thereafter, contralateral lung segments were challenged with allergen or saline. Using label-free quantitative proteomics, we comprehensively defined DE-mediated alteration of allergen-driven secreted proteins (secretome) in bronchoalveolar lavage. We further examined expression of proteins selected from the secretome data in independent validation experiments using Western blots, ELISA and immunohistochemistry.We identified protein changes unique to co-exposure (DE+allergen), undetected with mono-exposures (DE or allergen alone). Validation studies confirmed that specific proteins ( the antimicrobial peptide cystatin-SA) were significantly enhanced with DE+allergen compared to either mono-exposure.This study demonstrates that common environmental co-exposures can uniquely alter protein responses in the lungs, illuminating biology that mono-exposures cannot. This study highlights the value of complex human models in detailing airway responses to inhaled pollution.

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“…No sufficient data reported an anti-oxidant effect for cinnarizine, but anti-oxidants in general were recently reported to have good anti-asthmatic effects [53]. The anti-oxidant N-acetylcysteine was reported to decrease diesel-exhaust airway hyper-responsiveness clinically [54]. …”

Section: Discussionmentioning

confidence: 99%

Assessment of the Mechanistic Role of Cinnarizine in Modulating Experimentally-Induced Bronchial Asthma in Rats

2015

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Background/Aims: Calcium influx, inflammatory infiltration, cytokine production, immunoglobulin E activation and oxidative stress play coordinated roles in bronchial asthma pathogenesis. We aim to assess the protective effect of cinnarizine against experimentally induced bronchial asthma. Methods: Bronchial asthma was induced by ovalbumin sensitization and challenge. Rats were allocated into a normal control, an asthma control, a dexamethasone (standard) treatment, and 2 cinnarizine treatment groups. The respiratory functions tidal volume (TV) and peak expiratory flow rate (PEFR), the inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-5 (IL-5) in lung tissue, the allergic immunoglobulin IgE in serum, the absolute eosinophil count (AEC) in bronchoalveolar lavage fluid (BALF), as well as the oxidative and nitrosative markers glutathione reduced (GSH) and superoxide dismutase (SOD) in lung tissue and nitric oxide end products (NOx) in BALF were assessed, followed by a histopathological study. Results: Cinnarizine administration significantly restored TV, PEFR, TNF-α, IL-5, IgE, AEC, GSH, SOD and NOx values back to normal levels, and significantly decreased perivascular and peribronchiolar inflammatory scores. Conclusion: Cinnarizine may protect against experimental bronchial asthma. Suppressant effect of cinnarizine on pro-inflammatory cytokines release, IgE antibody production, eosinophil infiltration as well as oxidative and nitrosative stress may explain its anti-asthmatic potential.

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Anti-Oxidant N-Acetylcysteine Diminishes Diesel Exhaust-Induced Increased Airway Responsiveness in Person with Airway Hyper-Reactivity

Cited by 53 publications

References 34 publications

Diesel exhaust augments allergen-induced lower airway inflammation in allergic individuals: a controlled human exposure study

Diesel exhaust augments allergen-induced lower airway inflammation in allergic individuals: a controlled human exposure study

Inhaled diesel exhaust alters the allergen-induced bronchial secretome in humans

Assessment of the Mechanistic Role of Cinnarizine in Modulating Experimentally-Induced Bronchial Asthma in Rats

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