Hong Yong Peh, PhD
Pulmonary and Clinical Care Medicine
Hong Yong Peh*, Thayse Bruggemann, Melody Duvall, Robert Nshimiyimana, Maria Angeles Cinelli, Meghan N. Le, Elliott Israel, Charles Serhan, Bruce Levy
Background: Asthma is a chronic inflammatory disease without complete resolution. The production of specialized pro-resolving mediators (SPMs) is defective in asthma, so they represent a potential therapeutic opportunity. We hypothesize that the docosahexaenoic acid derived resolvin D2 (RvD2) can promote the resolution of allergic airway responses.
Methods: BALB/c mice were challenged intra-tracheally with house dust mite extract (HDM). Bronchoalveolar lavage (BAL) fluid was collected at predefined protocol endpoints for peak inflammation and during resolution. To determine impact on resolution, some mice were given RvD2 (100 ng (~0.005 mg/kg), intranasally) for 2 days after the last HDM challenge, and resolution indices for eosinophils, lung function, and inflammatory mediators were calculated. To deduce mechanistic actions of RvD2, expression of its receptor DRV2 was measured in mouse BAL cells and human whole blood, and a DRV2 competitive antagonist (O-1918) was used in the model.
Results: Airway exposure to HDM led to marked increases in BAL eosinophils and pro-inflammatory mediator levels. Histology demonstrated increases in airway inflammation and mucous cell metaplasia in HDM-challenged lungs. RvD2 significantly decreased BAL eosinophil and lymphocyte counts. The resolution interval for BAL eosinophils was markedly shortened with RvD2, and inflammatory changes to the bronchial epithelium, serum total IgE levels, BAL fluid proinflammatory cytokine levels, and methacholine-induced airway hyperresponsiveness were significantly decreased. DRV2 expression on mouse BAL leukocytes was enhanced after HDM and was also increased in asthmatic human peripheral blood eosinophils compared to healthy controls. RvD2-mediated actions were reversed by the DRV2 antagonist O-1918.
Conclusion: RvD2 promotes resolution of allergen-induced airway responses in a murine model of allergic asthma via DRV2, which is expressed on immune cells linked to asthma pathobiology.
Our findings point to a counter-regulatory role for RvD2-DRV2 signaling in allergic airway responses, so we would be interested to determine if asthma severity relates to this pathway. RvD2 can be considered as a potential treatment in asthma.