Cys-LTs’ Pro-phlogistic Lung Actions Are Regulated by Cys-Maresins

Abstract Background Cysteinyl leukotrienes (CysLTs) are potent pro-phlogistic mediators in asthma; however, inhibition of CysLT1 receptors is not a consistently effective treatment, suggesting additional regulatory mechanisms. Other cysteinyl-containing lipid mediators derived from docosahexaenoic acid (DHA), namely maresin conjugates of tissue regeneration (MCTRs), were recently discovered. Their production and actions in the lung are therefore of considerable interest. Objective To determine MCTR production, bioactions and mechanism in human lung and in experimental allergic airway inflammation. Methods Lipid mediator metabololipidomics profiling of lung was performed using liquid chromatography with tandem mass spectrometry. Donor-derived human precision cut lung slices (hPCLS) were exposed to leukotriene D4 (LTD4), MCTRs, or both, before determination of airway contraction. The actions of exogenous MCTRs on murine allergic host responses were determined in ovalbumin and house-dust-mite induced lung inflammation. Results Lipidomic profiling showed that the most abundant cysteinyl lipid mediators in healthy human lung were MCTRs whereas CysLTs were most prevalent in disease. MCTRs blocked LTD4-initiated airway contraction in hPCLS. In mouse allergic lung inflammation, MCTRs were present with temporally regulated production With ovalbumin-induced inflammation, MCTR1 was most potent for promoting resolution of eosinophils and MCTR3 potently decreased airway hyperreactivity to methacholine, bronchoalveolar lavage fluid albumin, and serum IgE levels. MCTR1 and MCTR3 inhibited lung eosinophilia after house dust mite-induced inflammation. Conclusion These results identified lung MCTRs that when added exogenously blocked human LTD4-induced airway contraction and promoted the resolution of murine allergic airway responses. Together, these findings uncover pro-resolving mechanisms for lung responses that may be disrupted in disease.