Air pollution, metabolic signatures, and the risk of idiopathic pulmonary fibrosis.

Air pollution has been associated with a higher incidence of idiopathic pulmonary fibrosis (IPF), yet this metabolic mechanism remains unclear. 185,865 participants were included in the UK Biobank. We estimated air pollution exposure using the bilinear interpolation approach, including fine particle matter with diameter < 2.5 μm (PM2.5), particle matter with diameter < 10 μm (PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOx). We identified metabolites and established the metabolic signature with air pollutants using an elastic net regularized regression. Cox proportional hazards models combined with generalized propensity score (GPS) were conducted to evaluate the relationships between metabolic signatures and incident IPF, and mediation analysis was performed to evaluate potential mediators. During a median follow-up of 12.3 years, 1239 IPF cases were ascertained. We identified multi-metabolite profiles comprising 87 metabolites for PM2.5, 65 metabolites for PM10, 71 metabolites for NO2, and 76 metabolites for NOx. Metabolic signatures were associated with incident IPF, with HRs of 1.20 (95 % CI: 1.13, 1.27), 1.09 (95 % CI: 1.03, 1.15), 1.23 (95 % CI: 1.16, 1.31), and 1.24 (95 % CI: 1.17, 1.31) per standard deviation (SD) increase in metabolic profiles associated with PM2.5, PM10, NO2, and NOx, respectively. Furthermore, metabolic signatures of PM2.5, PM10, NO2 and NOx significantly mediated 5.71 %, 3.98 %, 4.21 %, and 4.58 % of air pollution on IPF. Long-term air pollution was associated with a higher risk of IPF, with metabolites potentially playing a mediating role. The findings emphasize the significance of improving metabolic status for the prevention of IPF.