Lipid storm within the lungs of severe COVID-19 patients: Extensive levels of cyclooxygenase and lipoxygenase-derived inflammatory metabolites

Abstract

ABSTRACTBACKGROUNDSevere Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is the infectious agent responsible for Coronavirus disease 2019 (COVID-19). While SARS-CoV-2 infections are often benign, there are also severe COVID-19 cases, characterized by severe bilobar pneumonia that can decompensate to an acute respiratory distress syndrome, notably characterized by increased inflammation and a cytokine storm. While there is no cure against severe COVID-19 cases, some treatments significantly decrease the severity of the disease, notably aspirin and dexamethasone, which both directly or indirectly target the biosynthesis (and effects) of numerous bioactive lipids.OBJECTIVEOur working hypothesis was that severe COVID-19 cases necessitating mechanical ventilation were characterized by increased bioactive lipid levels modulating lung inflammation. We thus quantitated several lung bioactive lipids using liquid chromatography combined to tandem mass spectrometry.RESULTSWe performed an exhaustive assessment of the lipid content of bronchoalveolar lavages from 25 healthy controls and 33 COVID-19 patients necessitating mechanical ventilation. Severe COVID-19 patients were characterized by increased fatty acid levels as well as an accompanying inflammatory lipid storm. As such, most quantified bioactive lipids were heavily increased. There was a predominance of cyclooxygenase metabolites, notably TXB2 >> PGE2 ∼ 12-HHTrE > PGD2. Leukotrienes were also increased, notably LTB4, 20-COOH-LTB4, LTE4, and eoxin E4. 15-lipoxygenase metabolites derived from linoleic, arachidonic, eicosapentaenoic and docosahexaenoic acids were also increased. Finally, yet importantly, specialized pro-resolving mediators, notably lipoxin A4 and the D-series resolvins, were also found at important levels, underscoring that the lipid storm occurring in severe SARS-CoV-2 infections involves pro- and anti-inflammatory lipids.CONCLUSIONSOur data unmask the important lipid 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 lipids.