Transpulmonary eicosanoid metabolite gradients: insights into metabolic flux of pro- and anti-inflammatory metabolites and lung function

Introduction: Eicosanoids are upstream lipid mediators of inflammatory pathways. Transpulmonary gradient (ΔEIC) analysis using multisite sampling enables physiological assessment of metabolic flux across the lungs. While specific eicosanoids have been implicated in lung disease, the relationship between their metabolic flux and pulmonary physiology remains poorly understood. Methods: a directed nontargeted liquid chromatography-mass spectrometry platform. We quantified ΔEIC (ΔEIC=radial artery concentration-pulmonary artery concentration), indicating potential lung release or uptake, and examined associations of ΔEIC with spirometry parameters and lung disease. Results: Among 516 participants (mean age 57±15 years, 59% female), 68% had normal spirometry values, 19% had obstructive physiology and 13% had restrictive physiology. 10% had COPD and 7% had interstitial lung disease. Of 887 eicosanoids, 194 (22%) demonstrated significant ΔEIC, with 74% indicating pulmonary uptake (false discovery rate q<0.05). 10 ΔEIC were associated with lower odds of obstruction, including anti-inflammatory arachidonic acid derivatives (11/15-hydroxyeicosatetraenoic acid; 11,12/14,15-dihydroxyeicosatrienoic acid), prostaglandin G2 and leukotriene precursor 5S-hydroperoxyeicosatetraenoic acid, which were also associated with lower odds of COPD. Seven ΔEIC were associated with restriction, including anti-inflammatory docosahexaenoic acid derivative 10,11/13,14-dihydroxydocosapentaeonic acid, which was also associated with interstitial lung disease. Discussion: Using multisite sampling and molecular profiling, we identified specific eicosanoids with metabolic flux across the pulmonary circulation. Differential transpulmonary gradients of pro-inflammatory and anti-inflammatory eicosanoids were associated with abnormal lung function, underscoring potential relevance to chronic lung disease.