Cysteinyl maresins regulate the prophlogistic lung actions of cysteinyl leukotrienes

• Published in: Journal of allergy and clinical immunology Vol. 145; no. 1; pp. 335 - 344
• Main Authors: Levy, Bruce D., Abdulnour, Raja-Elie E., Tavares, Alexander, Brüggemann, Thayse R., Norris, Paul C., Bai, Yan, Ai, Xingbin, Serhan, Charles N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2020
• Subjects: Animals; asthma; Asthma - immunology; Asthma - pathology; Cysteine - antagonists & inhibitors; Cysteine - immunology; Docosahexaenoic Acids - immunology; Humans; inflammation; Leukotriene Antagonists - immunology; Leukotrienes - immunology; Lipidomics; lung; Lung - immunology; Lung - pathology; Mice; Resolution; AA; SPM-SC; LM; LT; GST; SPE; asthma; BAL; CysLT; lung; HDM; MCTR; LC-MS/MS; SPM; PCTR; inflammation; MaR1; DHA; hPCLS; Resolution; CysLT1
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2019.09.028

Cysteinyl leukotrienes (CysLTs) are potent prophlogistic mediators in asthmatic patients; however, inhibition of CysLT receptor 1 is not a consistently effective treatment, suggesting additional regulatory mechanisms. Other cysteinyl-containing lipid mediators (LMs) derived from docosahexaenoic acid, namely maresin conjugates in tissue regeneration (MCTRs), were recently discovered. Therefore their production and actions in the lung are of considerable interest. We sought to determine MCTR production, bioactions, and mechanisms in the human lung and in patients with experimental allergic airway inflammation. LM metabololipidomic profiling of the lung was performed by using liquid chromatography with tandem mass spectrometry. Donor-derived human precision-cut lung slices were exposed to leukotriene (LT) D4, MCTRs, or both before determination of airway contraction. The actions of exogenous MCTRs on murine allergic host responses were determined in the setting of ovalbumin- and house dust mite–induced lung inflammation. Lipidomic profiling showed that the most abundant cysteinyl LMs in healthy human lungs were MCTRs, whereas CysLTs were most prevalent in patients with disease. MCTRs blocked LTD4-initiated airway contraction in human precision-cut lung slices. 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. These results identified lung MCTRs that blocked human LTD4-induced airway contraction and promoted resolution of murine allergic airway responses when added exogenously. Together, these findings uncover proresolving mechanisms for lung responses that can be disrupted in patients with disease. [Display omitted]