Impact of Exposure to Diesel Exhaust on Inflammation Markers and Proteases in Former Smokers with Chronic Obstructive Pulmonary Disease: A Randomized, Double-blinded, Crossover Study.

Rationale: There is growing evidence that chronic obstructive pulmonary disease (COPD) can be caused and exacerbated by air pollution exposure. Objectives: To document the impact of short-term air pollution exposure on inflammation markers, proteases, and antiproteases in the lower airways of older adults with and without COPD. Methods: Thirty participants (10 ex-smokers with mild to moderate COPD and 20 healthy participants [9 ex-smokers and 11 never-smokers]), with an average age of 60 years, completed this double-blinded, controlled, human crossover exposure study. Each participant was exposed to filtered air (control) and diesel exhaust (DE), in washout-separated 2-hour periods, in a randomly assigned order. Bronchoscopy was performed 24 hours after exposure to collect lavage. Cell counts were performed on blood and airway samples. ELISAs were performed to measure acute inflammatory proteins, matrix proteinases, and antiproteases in the airway and blood samples. Measurements and Main Results: In former smokers with COPD, but not in the other participants, exposure to DE increased serum amyloid A (effect estimate, 1.67; 95% confidence interval [CI], 1.21-2.30; P = 0.04) and matrix metalloproteinase 10 (effect estimate, 2.61; 95% CI, 1.38-4.91; P = 0.04) in BAL. Circulating lymphocytes were increased after DE exposure (0.14 [95% CI, 0.05-0.24] cells × 109/L; P = 0.03), irrespective of COPD status. Conclusions: A controlled human crossover study of DE exposure reveals that former smokers with COPD may be susceptible to an inflammatory response compared with ex-smokers without COPD or never-smoking healthy control participants. Clinical trial registered with www.clinicaltrials.gov (NCT02236039).

Urinary Eicosanoid Levels Reflect Allergen and Diesel Exhaust Coexposure and Are Linked to Impaired Lung Function.

Eicosanoids are potent regulators of homeostasis and inflammation. Co-exposure to allergen and diesel exhaust (DE) have been shown to lead to eosinophilic inflammation, impaired airflow, and increased airway responsiveness. It is not clear whether eicosanoids mediate the mechanism by which these exposures impair lung function. We conducted a randomized, double-blinded, and four-arm crossover study. Fourteen allergen-sensitized participants were exposed to four conditions: negative control; allergen-alone exposure; DE and allergen coexposure; coexposure with particle-reducing technology applied. Quantitative metabolic profiling of urinary eicosanoids was performed using LC-MS/MS. As expected, allergen inhalation increased eicosanoids. The prostacyclin metabolite 2,3-dinor-6-keto-PGF1α (PGF1α, prostaglandin F1α) increased with coexposure, but particle depletion suppressed this pathway. Individuals with a high genetic risk score demonstrated a greater increase in isoprostane metabolites following coexposure. Causal mediation analyses showed that allergen induced airflow impairment was mediated via leukotriene E4 and tetranor-prostaglandin D metabolite. Overall, DE exposure did not augment the allergen's effect on urinary eicosanoids, except insofar as variant genotypes conferred susceptibility to the addition of DE in terms of isoprostane metabolites. These findings will add to the body of previous controlled human exposure studies and provide greater insight into how complex environmental exposures in urban air may influence individuals with sensitivity to aeroallergens.

Particle Depletion Does Not Remediate Acute Effects of Traffic-related Air Pollution and Allergen. A Randomized, Double-Blind Crossover Study.

Rationale: Diesel exhaust (DE), an established model of traffic-related air pollution, contributes significantly to the global burden of asthma and may augment the effects of allergen inhalation. Newer diesel particulate-filtering technologies may increase NO2 emissions, raising questions regarding their effectiveness in reducing harm from associated engine output.Objectives: To assess the effects of DE and allergen coexposure on lung function, airway responsiveness, and circulating leukocytes, and determine whether DE particle depletion remediates these effects.Methods: In this randomized, double-blind crossover study, 14 allergen-sensitized participants (9 with airway hyperresponsiveness) underwent inhaled allergen challenge after 2-hour exposures to DE, particle-depleted DE (PDDE), or filtered air. The control condition was inhaled saline after filtered air. Blood sampling and spirometry were performed before and up to 48 hours after exposures. Airway responsiveness was evaluated at 24 hours.Measurements and Main Results: PDDE plus allergen coexposure impaired lung function more than DE plus allergen, particularly in those genetically at risk. DE plus allergen and PDDE plus allergen each increased airway responsiveness in normally responsive participants. DE plus allergen increased blood neutrophils and was associated with persistent eosinophilia at 48 hours. DE and PDDE each increased total peripheral leukocyte counts in a manner affected by participant genotypes. Changes in peripheral leukocytes correlated with lung function decline.Conclusions: Coexposure to DE and allergen impaired lung function, which was worse after particle depletion (which increased NO2). Thus, particulates are not necessarily the sole or main culprit responsible for all harmful effects of DE. Policies and technologies aimed at protecting public health should be scrutinized in that regard.Clinical trial registered with www.clinicaltrials.gov (NCT02017431).