Dose-dependent effect of ethanolamine of eicosapentaenoic acid on the synthesis of oxylipins by blood cells of patients with bronchial asthma in vitro

Introduction. The search for new highly effective methods for the treatment and control of bronchial asthma is an urgent task in pathophysiology and pharmacology. A promising substance for the regulation of systemic chronic inflammation is N-acylethanolamine (EPEA) of eicosapentaenoic acid, which exhibits immunoregulatory properties.

Aim. To study the dose-dependent effect of eicosapentaenoic acid ethanolamine on the synthesis and metabolism of oxylipins by blood cells in patients with asthma under in vitro conditions.

Materials and methods. The object of the study was the whole blood of 5 patients with controlled mild-to-moderate asthma and 6 healthy people. The in vitro experiment was carried out in lipopolysaccharide-stimulated blood after incubation for 30 minutes. Then the experimental substance N-acyl-ethanolamine of eicosapentaenoic acid (NAE 20:5) was added at concentrations of 1.0, 5.0 and 10.0 µM and incubated at 37ºC for 6 hours in gentle mixing mode. The level of oxylipins was studied by enzyme immunoassay.

Results. Experimental exposure to N-acylethanolamines of eicosapentenoic acid had the following effects. Under the influence of ethanolamine of eicosapentaenoic acid at a concentration of 1 µM, the level of PGE2 decreased by 51% (p<0.001) and the amount of 15-HEPE increased by 32% (p<0.05) in lipopolysaccharide-induced blood plasma relative to the values before exposure to ethanolamine. Also EPEA at this dosage showed a tendency to increase the level of 18HEPE. Exposure to EPEA at 5µM resulted in a significant decrease in LTB4 levels by 34% (p<0.001), PGE2 levels by 51% (p<0.001), as well as an increase in 12-HEPE levels by 33% (p<0.01), 15-HEPE by 36% (p<0.05) and 18-HEPE by 87% (p<0.01). Under the influence of EPEA at a dosage of 10 µM, a statistically significant effect on the entire spectrum of the studied oxylipins was revealed. Thus, the use of this dose of ethanolamide in LPS-induced blood showed a decrease in the concentration of LTB4 by 37% (p<0.001), LXA4 by 22% (p<0.05), PGE2 by 50% (p<0.001) and an increase in 5HEPE concentration by 25% (p<0.05), 12-HEPE by 76% (p<0.001), 15-HEPE by 75% (p<0.001), 18-HEPE by 155% (p<0.001) relative to pre-EPEA values.

Conclusion. Further study of NAE fatty acids opens up new perspectives in the study of targeted methods for correcting the inflammatory response in bronchial asthma.

1. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. 2023. Available at: https://ginasthma.org

2. Misheva M., Johnson J., McCullagh J. Role of Oxylipins in the Inflammatory-Related Diseases NAFLD, Obesity, and Type 2 Diabetes. Metabolites 2022; 12(12):1238. https://doi.org/10.3390/metabo12121238

3. Trinh H.K.T., Lee S.H., Cao T.B.T., Park H.S. Asthma pharmacotherapy: an update on leukotriene treatments. Expert Rev. Respir. Med. 2019; 13(12):1169‒1178. https://doi.org/10.1080/17476348.2019.1670640

4. Saturnino C., Popolo A., Ramunno A., Adesso S., Pecoraro M., Plutino M.R., Rizzato S., Albinati A., Marzocco S., Sala M., Iacopetta D., Sinicropi M.S. Anti-Inflammatory, Antioxidant and Crystallographic Studies of N-Palmitoyl-ethanol Amine (PEA) Derivatives. Molecules 2017; 22(4):616. https://doi.org/10.3390/molecules22040616

5. Liang L., Takamiya R., Miki Y., Heike K., Taketomi Y., Sugimoto N., Yamaguchi M., Shitara H., Nishito Y., Kobayashi T., Hirabayashi T., Murakami M. Group IVE cytosolic phospholipase A2 limits psoriatic inflammation by mobilizing the anti-inflammatory lipid N-acylethanolamine. FASEB J. 2022; 36(5):e22301. https://doi.org/10.1096/fj.202101958R

6. Balvers M.G., Verhoeckx K.C., Plastina P., Wortelboer H.M., Meijerink J., Witkamp R.F. Docosahexaenoic acid and eicosapentaenoic acid are converted by 3T3-L1 adipocytes to N-acyl ethanolamines with anti-inflammatory properties. Biochim. Biophys. Acta 2010;1801(10):1107‒1114. https://doi.org/10.1016/j.bbalip.2010.06.006

7. McDougle D.R., Watson J.E., Abdeen A.A., Adili R., Caputo M.P., Krapf J.E., Johnson R.W., Kilian K.A., Holinstat M., Das A. Anti-inflammatory ω-3 endocannabinoid epoxides Anti-inflammatory ω-3 endocannabinoid epoxides. Proc. Natl Acad. Sci. USA 2017; 114(30):E6034-E6043. https://doi.org/10.1073/pnas.1610325114

8. Carnevale L.N., Das A. Novel Anti-inflammatory and Vasodilatory ω-3 Endocannabinoid Epoxide Regioisomers. Adv. Exp. Med. Biol. 2019; 1161:219‒232. https://doi.org/10.1007/978-3-030-21735-8_17

9. Kytikova O.Y., Antonyuk M.V., Gvozdenko T.A., Novgorodtseva T.Р. [Metabolic aspects of the relationship of asthma and obesity]. Obesity and metabolism 2018; 15(4):9‒14 (in Russian). https://doi.org/10.14341/omet9578

10. Patel D., Witt S.N. Ethanolamine and Phosphatidylethanolamine: Partners in Health and Disease. Oxid. Med. Cell. Longev. 2017; 2017:4829180. https://doi.org/10.1155/2017/4829180