High levels of eicosanoids and docosanoids in the lungs of intubated COVID-19 patients

Abstract

Severe acute respiratory syndrome coronavirus 2 is responsible for coronavirus disease 2019 (COVID-19). While COVID-19 is often benign, a subset of patients develops severe multilobar pneumonia that can progress to an acute respiratory distress syndrome. There is no cure for severe COVID-19 and few treatments significantly improved clinical outcome. Dexamethasone and possibly aspirin, which directly/indirectly target the biosynthesis/effects of numerous lipid mediators are among those options. Our objective was to define if severe COVID-19 patients were characterized by increased bioactive lipids modulating lung inflammation. A targeted lipidomic analysis of bronchoalveolar lavages (BALs) by tandem mass spectrometry was done on 25 healthy controls and 33 COVID-19 patients requiring mechanical ventilation. BALs from severe COVID-19 patients were characterized by increased fatty acids and inflammatory lipid mediators. There was a predominance of thromboxane and prostaglandins. Leukotrienes were also increased, notably LTB₄ , LTE₄ , and eoxin E₄ . Monohydroxylated 15-lipoxygenase metabolites derived from linoleate, arachidonate, eicosapentaenoate, and docosahexaenoate were also increased. Finally yet importantly, specialized pro-resolving mediators, notably lipoxin A₄ and the D-series resolvins, were also increased, underscoring that the lipid mediator storm occurring in severe COVID-19 involves pro- and anti-inflammatory lipids. Our data unmask the lipid mediator storm occurring in the lungs of patients afflicted with severe COVID-19. We discuss which clinically available drugs could be helpful at modulating the lipidome we observed in the hope of minimizing the deleterious effects of pro-inflammatory lipids and enhancing the effects of anti-inflammatory and/or pro-resolving lipid mediators.

Keywords: COVID-19; docosanoids; eicosanoids; eoxins; specialized pro-resolving mediators; thromboxane.

FIGURE 1

Levels of eicosanoids in the BAL fluids of healthy and COVID‐19 patients. BALs were obtained and processed as described in Methods. Lipids then were extracted and quantitated by LC‐MS/MS. A, Metabolism of arachidonic acid (AA) by the cyclooxygenase (COX) pathway. B, AA levels. C,D, Levels of COX‐derived metabolites. E, Leukotriene (LT) biosynthetic pathways. F,G, Levels of LTs and eoxins (EX). H, Metabolism of AA and eicosapentaenoic acid (EPA) by 5‐, 12‐, and 15‐lipoxygenase (LO). I,J, Levels of LO‐derived metabolites of AA. K, EPA levels. L, Levels of LO‐derived EPA metabolites. L, Proportions of eicosanoids from panel C, D, F, G, I, and K. Results are from the BALs of 25 healthy subjects and 33 COVID‐19 patients. P values were obtained by performing a Mann‐Whitney test using the GraphPad Prism 9 software: *** = P < .001, **** = P < .0001

FIGURE 2

Levels of docosanoids in the BAL fluids of healthy and COVID‐19 patients. BALs were obtained and processed as described in Methods. Lipids then were extracted and quantitated by LC‐MS/MS. A, Docosanoid biosynthetic pathways. B, Levels of docosapentaenoic acid n‐3 (DPAn‐3) and docosahexaenoic acid (DHA). C,D, Docosanoid levels. E, Proportions of the different docosanoids from panel C and D. Results are from the BALs from 25 healthy subjects and 33 COVID‐19 patients. P values were obtained by performing a Mann‐Whitney test using the GraphPad Prism 9 software: * = P < .05, ** = P < .01, *** = P < .001, **** = P < .0001

FIGURE 3

Levels of lipid mediators derived from linoleic acid (LA), α‐linolenic acid or dihomo‐γ‐linolenic acid (DGLA) in the BAL fluids of healthy and COVID‐19 patients. BALs were obtained and processed as described in Methods. Lipids then were extracted and quantitated by LC‐MS/MS. A, Metabolism of LA, ALA, and DGLA by the 12/15‐lipoxygenase (LO) pathways. B, Levels of LA. C,D, Levels of oxidized mediators from LA, ALA, and DGLA. Results are from the BALs from 25 healthy subjects and 33 COVID‐19 patients. P values were obtained by performing a Mann‐Whitney test using the GraphPad Prism 9 software: **** = P < .0001

FIGURE 4

Correlation between bioactive lipid mediators in the BALs of COVID‐19 patients. A Spearman correlation matrix between the different lipid mediators is shown. Positive correlations are shown using shades of blue. P < .05 was the threshold of significance and non‐significant correlations (P > .05) are marked by an X

FIGURE 5

Correlation between bioactive lipids in the BALs of COVID‐19 patients and clinical parameters. A non‐parametric Spearman correlation matrix between Lipid mediators and clinical parameters was done using the corrplot package. Positive correlations are shown using shades of blue and negative correlations are shown using shades of red. P < .05 was the threshold of significance and non‐significant correlations (P > .05) are marked by an X