Lower Plasma Resolvin D1 Level and Greater Sputum Eosinophilia Characterize a Cluster of Severe Asthma Patients

Severe asthma is a chronic disease of airway inflammation with substantial morbidity. Deficient specialized pro-resolving mediators (SPMs) are associated with persistent airway inflammation and impaired lung function in some patients with severe asthma. Resolvin D1 (RvD1) is an SPM agonist for inflammation resolution. Plasma RvD1 was measured longitudinally over 5 years in 23 severe asthma patients in the Severe Asthma Research Program (SARP) to identify relationships between clinical parameters, type 2 inflammation, and sputum gene expression. The majority of severe asthma patients had persistently low plasma RvD1; a smaller subgroup had higher RvD1 that fluctuated over time. Correlation analysis indicated a relationship between plasma RvD1 and sputum eosinophilia. A subgroup of severe asthma patients had low plasma RvD1 and high sputum eosinophils (RvD1LoSpEosHi); a separate subgroup had high plasma RvD1 and low sputum eosinophils (RvD1HiSpEosLo). The RvD1LoSpEosHi patient cluster had increased T2 inflammation, lower lung function, and more asthma exacerbations. 42 genes were differentially expressed in RvD1LoSpEosHi severe asthma sputum, including hypoxia-inducible factor 1-alpha (HIF1A). RvD1 significantly downregulated eosinophil HIF-1α expression in vitro. These findings identify a subset of severe asthma patients with low RvD1 and increased sputum eosinophilia, and RvD1 regulation of eosinophil activation ex vivo, suggesting a counter-regulatory role for this SPM in modulating eosinophilic T2 inflammation in asthma.