Impact of Short-Term Diesel Exhaust Exposure on Prothrombotic Markers in COPD: A Randomized, Double-blinded, Crossover Study.

ABSTRACT

Rationale Growing evidence suggests that air pollution exposure is a major risk factor in chronic obstructive pulmonary disease (COPD) that is associated with an increased prothrombotic state and adverse cardiovascular outcomes. However, much of this work is based on observational data or human exposure studies involving younger participants. The biological causality and mechanism of air pollution-induced prothrombotic response in patients with COPD remain to be explored. Objective: The main aim of this work was to investigate the impact of short-term diesel exhaust (DE) exposure on circulating prothrombotic markers-fibrinogen and plasminogen activator inhibitor-1 (PAI-1)-and urinary eicosanoids in patients with COPD. Methods: Twenty-nine research participants were recruited in this randomized, double-blinded, crossover, controlled human exposure study to DE. Participants included former smokers with and without mild or moderate COPD (ES and COPD group) and healthy never-smokers without COPD (NS group). Each participant was exposed to DE (300 µg/m3 of PM2.5) and filtered air (FA) for 2 hours on different occasions, in randomized order, separated by a 4-week washout. Blood and urine samples were collected prior to and 24 hours after each exposure. Plasma fibrinogen and serum PAI-1 concentrations were quantified using ELISAs. Urinary eicosanoid concentrations were quantified using ultra- performance liquid chromatography coupled to tandem mass spectrometry. Linear mixed-effects models were used for statistical comparisons. Results: Participants with COPD showed an increase in plasma fibrinogen (effect estimate 1.27 [1.06 to 1.53], p=0.01) after DE relative to FA, but no significant DE-associated change in serum PAI-1 (0.95 [0.87 to 1.04], p=0.26). In never-smokers and ex-smokers without COPD, fibrinogen (NS group 1.10 [0.99 to 1.23], p=0.08; ES group 0.86 [0.68 to 1.09], p=0.08] and PAI-1 (NS group 1.12 [ 0.96 to 1.32], p=0.15; ES group 0.90 [0.79 to 1.03], p=0.13) were not changed after DE exposure. COPD participants showed a DE-attributable increase in urinary thromboxane B2 (TXB2) metabolites concentrations as follows 11-dehydro TXB2 (1.45 [1.02 to 2.08], p=0.04); 2,3-dinor-TXB2 (1.45 [1.05 to 2.00], p=0.03). Conclusions: Participants with COPD had increased plasma fibrinogen and urinary TXB2 metabolites after short-term DE exposure, suggesting they may be more susceptible to pollution-attributable prothrombotic response compared to healthy controls or ex-smokers without COPD. Clinical trial registration available at www.clinicaltrials.gov, ID NCT02236039.