Abstract / Summary
Abstract Background. Traffic-derived particulate triggers cardiorespiratory events within hours, a latency more compatible with a neurogenic than an inflammatory mechanism. The transient receptor potential vanilloid 1 (TRPV1) channel on bronchopulmonary vagal C-fibres is the candidate interface: it is directly activated by diesel exhaust particles (DEP) in vitro and is highly polymorphic. Whether DEP modulates TRPV1 function in humans in vivo, and whether genotype modifies that response, is unknown. Methods. Twenty-three healthy non-smoking adults (12 men; 32.6 ± 8.6 years) completed a randomised, double-blind, two-period crossover inhalation study comparing a standardised DEP suspension (SRM 2975; 288 µg delivered dose) with its diluent, by dosimeter-controlled nebulisation. Capsaicin cough challenge, heart rate variability, blood pressure and redox biomarkers were assessed, and an additive capsaicin-responsiveness score was derived from four informative TRPV1 loci. Within-person contrasts used permutation-based paired t tests with Benjamini–Hochberg adjustment; genotype effect modification was examined in Bayesian multilevel and covariate-adjusted models. Results. Compared with diluent, DEP halved the capsaicin concentration evoking two coughs (79.8 vs 155.1 µM; p = 0.029), raised the LF/HF ratio from 1.07 to 1.87 (p = 0.005) with a reciprocal shift in normalised low- and high-frequency power (both q = 0.030) and unchanged heart rate, and increased systolic blood pressure (p = 0.040). Biological antioxidant potential and the redox index fell (both q < 0.001), hydroperoxides unchanged. No outcome differed between diluent and baseline. The exposure-by-score interaction was credible for rMSSD (β = −0.32; 95% CrI − 0.54 to − 0.10) but not for log C2, and survived adjustment for the post-diluent value, sequence, washout, age and sex (β = −0.26; 95% CrI − 0.49 to − 0.02). Conclusions. A single inhaled dose of diesel particulate, below the elemental carbon burden of one working shift at the current occupational limit, sensitised airway TRPV1, tilted cardiac autonomic balance towards sympathetic predominance and consumed antioxidant defences in healthy adults. This first human demonstration of a pathway hitherto confined to cells and animals unfolds on the same timescale as the excess of cardiovascular events following pollution peaks. Susceptibility was genetically graded: the vagal displacement scaled with the burden of capsaicin-responsive TRPV1 alleles, variants that are silent towards indirect endogenous sensitisers. TRPV1 genotype thus emerges as a candidate susceptibility biomarker for traffic-exposed populations.