Inhalation of allergen and diesel exhaust increases urinary eicosanoids
associated with impaired lung function and airway hyperresponsiveness: a
randomized, double-blinded, human crossover study
Abstract
Background. Eicosanoids are potent regulators of homeostasis
and inflammation that play an important role in asthma pathophysiology.
In a controlled human exposure study, we showed that coexposure to an
allergen and diesel exhaust (DE) led to eosinophilic inflammation,
impaired airflow, and increased airway responsiveness. Eicosanoids may
mediate the mechanism by which these exposures impair lung function.
Methods. We conducted a randomized, double-blinded, four-arm
crossover study. Fourteen allergen-sensitized participants were exposed
to four conditions: filtered air and saline (FA-S; negative control);
filtered air and allergen (FA-A; allergen alone); DE and allergen (DE-A;
coexposure); and particle-depleted DE and allergen (PDDE-A; coexposure
with minimal particles). Quantitative metabolic profiling of urinary
eicosanoids was performed using LC-MS/MS. Results. Allergen
inhalation increased urinary eicosanoids. The prostacyclin metabolite
2,3-dinor-6-keto-PGF1α increased with DE-A, but particle
depletion (PDDE-A) suppressed this pathway. Baseline airway
hyperresponsiveness modified the allergen-induced increase in
prostaglandin D2 metabolites (tetranor PGDM and
2,3-dinor-11β-PGF2α) such that normally responsive
individuals showed a greater allergen-induced increase of the two
metabolites. Genetic risk scores (GRS) modified the effect of DE-A;
those individuals with a high GRS demonstrated a greater increase in
isoprostane metabolites following DE-A. Increased urinary leukotriene
E4 and tetranor PGDM correlated with increased airway
responsiveness, while increased tetranor PGDM also correlated with
decline in FEV1. Conclusions. Impaired airflow
and increased airway responsiveness upon exposure to DE-A may be
attributable to increased levels of leukotrienes and prostaglandins.
Variants in genes known to mediate response to pollution appear to
modulate these eicosanoid-mediated physiological responses known to
contribute to asthma pathophysiology.