Plasma Linoleate Diols Are Potential Biomarkers for Severe COVID-19 Infections

Abstract

Polyunsaturated fatty acids are metabolized into regulatory lipids important for initiating inflammatory responses in the event of disease or injury and for signaling the resolution of inflammation and return to homeostasis. The epoxides of linoleic acid (leukotoxins) regulate skin barrier function, perivascular and alveolar permeability and have been associated with poor outcomes in burn patients and in sepsis. It was later reported that blocking metabolism of leukotoxins into the vicinal diols ameliorated the deleterious effects of leukotoxins, suggesting that the leukotoxin diols are contributing to the toxicity. During quantitative profiling of fatty acid chemical mediators (eicosanoids) in COVID-19 patients, we found increases in the regioisomeric leukotoxin diols in plasma samples of hospitalized patients suffering from severe pulmonary involvement. In rodents these leukotoxin diols cause dramatic vascular permeability and are associated with acute adult respiratory like symptoms. Thus, pathways involved in the biosynthesis and degradation of these regulatory lipids should be investigated in larger biomarker studies to determine their significance in COVID-19 disease. In addition, incorporating diols in plasma multi-omics of patients could illuminate the COVID-19 pathological signature along with other lipid mediators and blood chemistry.

Eicosanoid Metabolomic Profile of Remdesivir Treatment in Rat Plasma by High-Performance Liquid Chromatography Mass Spectrometry

“…As reported by Schwarz et al (2021) , compared with the healthy condition, the lipid mediators and eicosanoids were disturbed, including decreased products of ALOX12 (e.g., 12-HEPE, 12-HETE, RvE3, and LXA4) and COX2 (e.g., PGE2, PGD2, PGF2a, TXB2, and 18-HEPE), increase products of ALOX5 (e.g., RvD1-4, LTB4, 5-HEPE, 5-HETE, 7-HDHA, and 7-HDPA), and cytochrome p450 (5,6 DiHETrE, 8,9 DiHETrE, 11,12 DiHETrE, and 14,15 DiHETrE) in human serum. Besides, plasma metabolic results identified 18 metabolites (e.g., LTB4, 9,10-DiHOME, 12,13-DiHOME, PGE2, and PGD2) with statistically significant differences ( p < 0.01) with more than four-fold change between healthy controls ( n = 44) and COVID-19 patients ( n = 6) ( McReynolds et al, 2021 ). Much works, either in vitro or in vivo , may be necessitated to evaluate metabolomic characteristics under virus attack.…”

Blood Fatty Acids Profile in MIS-C Children

“…Together with cytokines, lipid mediators also play a critical role in the physiological evolution of the acute inflammatory reaction: oxygenated metabolites arising from ω6 PUFA may participate in both the propagation and the resolution of the inflammatory response [44], but they mainly exert potent proinflammatory and prothrombotic activities. Indeed, specifically targeting the production and the activity of AA-derived leukotrienes has been proposed as a novel approach to modulate the hyperinflammatory state in COVID-19 subjects [27], and increased concentrations of LA-derived leukotoxin diols were detected in the plasma of severe COVID-19 patients [45]. On the other hand, ω3 PUFA (i.e., EPA and DHA) are the substrates responsible for the formation of a new genus of anti-inflammatory and pro-resolution lipid mediators collectively named specialized pro-resolving mediators (SPM) [23,24].…”

A Soluble Epoxide Hydrolase Inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) Urea, Ameliorates Experimental Autoimmune Encephalomyelitis

“…Although sEH induction and subsequent DiHOME production are involved in thermogenesis in brown fat adipose [ 41 ], diols of linoleate at high concentrations induce deleterious consequences in vascular and pulmonary permeability [ 40 ]. Importantly, the plasma levels of 12,13-DiHOME were associated with severe cases of COVID-19 (coronavirus disease 2019) [ 42 ], further supporting the detrimental effects of 12,13-DiHOME in respiratory failure. Since TPPU significantly and robustly reduced the toxic 12,13-DiHOME in EAE plasma and SCs, inhibition of this pathway might be a key mechanism for TPPU’s preventative effects.…”