MS-based targeted profiling of oxylipins in COVID-19: A new insight into inflammation regulation

Abstract

The key role of inflammation in COVID-19 induced many authors to study the cytokine storm, whereas the role of other inflammatory mediators such as oxylipins is still poorly understood. IMPRECOVID was a monocentric retrospective observational pilot study with COVID-19 related pneumonia patients (n = 52) admitted to Pisa University Hospital between March and April 2020. Our MS-based analytical platform permitted the simultaneous determination of sixty plasma oxylipins in a single run at ppt levels for a comprehensive characterisation of the inflammatory cascade in COVID-19 patients. The datasets containing oxylipin and cytokine plasma levels were analysed by principal component analysis (PCA), computation of Fisher’s canonical variable, and a multivariate receiver operating characteristic (ROC) curve. Differently from cytokines, the panel of oxylipins clearly differentiated samples collected in COVID-19 wards (n = 43) and Intensive Care Units (ICUs) (n = 27), as shown by the PCA and the multivariate ROC curve with a resulting AUC equal to 0.92. ICU patients showed lower (down to two orders of magnitude) plasma concentrations of anti-inflammatory and pro-resolving lipid mediators, suggesting an impaired inflammation response as part of a prolonged and unsolvable pro-inflammatory status. In conclusion, our targeted oxylipidomics platform helped shedding new light in this field. Targeting the lipid mediator class switching is extremely important for a timely picture of a patient’s ability to respond to the viral attack. A prediction model exploiting selected lipid mediators as biomarkers seems to have good chances to classify patients at risk of severe COVID-19.

Plasma Oxylipins and Their Precursors Are Strongly Associated with COVID-19 Severity and with Immune Response Markers

“…The elevated HETEs and three prostanoids also correlated with IL-7 (e.g., TXB2 in Figure 4 d), possibly reflecting increased blood cell count. COVID-19 studies found that compared to patients in the ward, ICU patients had lower levels of the same prostanoids as we recorded [ 7 ], or of PGE2, PGD2, and several HETEs [ 5 ]. In comparable conditions, ICU sepsis non-survivors showed reduced PGE2, PGD2, and TXB2 compared to survivors [ 54 ].…”

“…We found a strong correlation between the isoprostane, TNF-alpha, and macrophage activation markers. Several isoprostanoids were elevated in COVID-19 ICU patients in another study [ 5 ], potentially indicating the oxidative stress that accompanies inflammation in critically ill patients, especially those who suffer ARDS [ 52 ]. ROS dysregulation can further contribute to endothelial dysfunction, since redox reactions affect cell adhesion, platelet aggregation, vasoconstriction, inflammatory gene expression, and more [ 53 ].…”

“…In contrast, neither DHA nor its HDHA derivatives, which are precursors of many SPMs, were higher in ICU patients. Other COVID-19 studies reported severity-dependent downregulation of DHA-derived SPMs [ 5 , 9 ], together with a shift in the expression of LOX enzymes [ 9 ]. In contrast, SPMs increased in the serum of COVID-19 patients compared to healthy controls [ 10 ].…”

“…A persistent and excessive innate immune response contributes to COVID-19 severity. Various lipids, some acting as immune modulators, are dysregulated along the course of the disease [ 1 , 2 , 3 , 4 , 5 , 6 ], yet obtaining an exact metabolic picture of small lipids involvement is still work in progress [ 5 , 7 , 8 , 9 , 10 ]. Low molecular weight lipids (<500 Da) play diverse biochemical roles, as they are embedded in cell membranes and take part in cell signalling, energy production and storage, among other endogenous processes.…”

OxInflammation at High Altitudes: A Proof of Concept from the Himalayas

“…The supernatant was then diluted (1:6 v / v ) with water and subjected to MEPS extraction. The methanolic extract was directly injected into the UHPLC-MS/MS system and oxylipins were analyzed as described elsewhere [ 33 ].…”