К вопросу о липоксинах как липидных медиаторах разрешения воспаления на примере бронхиальной астмы

Бронхиальная астма (БA) представляет собой важнейшую медико-социальную проблему современности в связи с широкой распространённостью, хроническим течением и  гетерогенностью, определяющими сложность лечения данного заболевания. Хроническое воспаление, характерное для БА, сопровождается развитием дисбаланса между провоспалительными, противовоспалительными и  проразрешающими липидными медиаторами, продуцируемыми омега-3 (ω-3) и  омега-6 (ω-6) полиненасыщенными жирными кислотами. Наибольший исследовательский интерес прикован к  проразрешающим липидным медиаторам, в  частности к  липоксинам. С одной стороны, пути метаболизма и рецепторы липоксинов, такие как N-формилпептидный рецептор 2-го типа и ядерный рецептор ароматических углеводородов, могут стать основой для новых подходов к лечению БА, нацеленных на  процессы разрешения воспаления. С  другой стороны, данные медиаторы образуются в  очень незначительном количестве и являются достаточно нестабильными в сравнении с другими липидными медиаторами разрешения воспаления. Сложности обнаружения липоксинов лимитируют их изучение, а также ставят под вопрос значимость их роли в разрешении воспаления при БА.

Цель обзора. Обобщить современные представления о  роли липидных медиаторов разрешения воспаления – липоксинов – в патогенезе бронхиальной астмы на основании анализа статей, опубликованных на английском языке до 2023 г. в базе данных PubMed.

В  настоящем обзоре обсуждаются противоречивость существующих взглядов на  роль липоксинов в  качестве проразрешающих медиаторов и потенциальные терапевтические преимущества нацеливания на рецепторы липоксинов.

1. Panigrahy D, Gilligan ММ, Serhan CN, Kashfi K. Resolution of inflammation: An organizing principle in biology and medicine. Pharm Ther. 2021; 227: 107879. doi: 10.1016/j.pharmthera.2021.107879

2. Park J, Langmead CJ, Riddy DM. New advances in targeting the resolution of inflammation: Implications for specialized proresolving mediator GPCR drug discovery. ACS Pharmacol Transl Sci. 2020; 3: 88-106. doi: 10.1021/acsptsci.9b00075

3. Global Initiative for Asthma. (GINA). Global strategy for asthma management and prevention. 2020. URL: http://ginasthma.com [date of access: 29.11.2023].

4. Xu X, Li J, Zhang Y, Zhang L. Arachidonic acid 15-lipoxygenase: Effects of its expression, metabolites, and genetic and epigenetic variations on airway inflammation. Allergy Asthma Immunol Res. 2021; 13(5): 684-696. doi: 10.4168/aair.2021.13.5.684

5. Bayani A, Dunster JL, Crofts JJ, Nelson MR. Mechanisms and points of control in the spread of inflammation: A mathematical investigation. Bull Math Biol. 2020; 82(4): 45. doi: 10.1007/s11538-020-00709-y

6. Venter C, Meyer RW, Nwaru BI, Roduit C, Untersmayr E, Adel-Patient K, et al. EAACI position paper: Influence of dietary fatty acids on asthma, food allergy, and atopic dermatitis. Allergy. 2019; 74(8): 1429-1444. doi: 10.1111/all.13764

7. Zhu Z, Camargo CA Jr, Hasegawa K. Metabolomics in the prevention and management of asthma. Expert Rev Respir Med. 2019; 13(12): 1135-1138. doi: 10.1080/17476348.2019.1674650

8. Ni KD, Liu JY. The functions of cytochrome P450 omegahydroxylases and the associated eicosanoids in inflammationrelated diseases. Front Pharmacol. 2021; 12: 716801. doi: 10.3389/fphar.2021.716801

9. Vishnupriya P, Aparna A, Viswanadha VP. Lipoxygenase (LOX) pathway: A promising target to combat cancer. Curr Pharm Des. 2021; 27(31): 3349-3369. doi: 10.2174/1381612826666210101153216

10. Kytikova OY, Novgorodtseva TP, Antonyuk MV, Denisenko YK, Gvozdenko T. Pro-resolving lipid mediators in the pathophysiology of asthma. Medicina (Kaunas). 2019; 18(55): 284. doi: 10.3390/medicina55060284

11. Margină D, Ungurianu A, Purdel C, Nițulescu GM, Tsoukalas D, Sarandi E, et al. Analysis of the intricate effects of polyunsaturated fatty acids and polyphenols on inflammatory pathways in health and disease. Food Chem Toxicol. 2020; 143: 111558. doi: 10.1016/j.fct.2020.111558

12. Julliard WA, Myo YPA, Perelas A, Jackson PD, Thatcher TH, Sime PJ. Specialized pro-resolving mediators as modulators of immune responses. Semin Immunol. 2022; 59: 101605. doi: 10.1016/j.smim.2022.101605

13. Cagnina RE, Duvall MG, Nijmeh J, Levy BD. Specialized proresolving mediators in respiratory diseases. Curr Opin Clin Nutr Metab Care. 2022; 25(2): 67-74. doi: 10.1097/MCO.0000000000000805

14. Kahnt AS, Schebb NH, Steinhilber D. Formation of lipoxins and resolvins in human leukocytes. Prostaglandins Other Lipid Mediat. 2023; 166: 106726. doi: 10.1016/j.prostaglandins.2023.106726

15. Krishnamoorthy N, Abdulnour RE, Walker KH, Engstrom BD, Levy BD. Specialized proresolving mediators in innate and adaptive immune responses in airway diseases. Physiol Rev. 2018; 98(3): 1335-1370. doi: 10.1152/physrev.00026.2017

16. Serhan CN. The resolution of inflammation: The devil in the flask and in the details. FASEB J. 2011; 25(5): 1441-1448. doi: 10.1096/fj.11-0502ufm

17. Jordan PM, Werz O. Specialized pro-resolving mediators: Biosynthesis and biological role in bacterial infections. FEBS J. 2022; 289(14): 4212-4227. doi: 10.1111/febs.16266

18. Powell WS. Eicosanoid receptors as therapeutic targets for asthma. Clin Sci (Lond). 2021; 135(16): 1945-1980. doi: 10.1042/CS20190657

19. Serna MF, Mosquera Escudero M, García-Perdomo HA. Lipoxins and their relationship with inflammation-associated diseases. A systematic review. Obes Res Clin Pract. 2023; 17(4): 298-307. doi: 10.1016/j.orcp.2023.06.001

20. Maciuszek M, Cacace A, Brennan E, Godson C, Chapman TM. Recent advances in the design and development of formyl peptide receptor 2 (FPR2/ALX) agonists as pro-resolving agents with diverse therapeutic potential. Eur J Med Chem. 2021; 213: 113167. doi: 10.1016/j.ejmech.2021.113167

21. Ismael A, Zeeshan M, Hansen JH. Synthesis of aromatic lactone analogues of lipoxin A4. BMC Res Notes. 2022; 15(1): 30. doi: 10.1186/s13104-022-05917-4

22. De Gaetano M, Butler E, Gahan K, Zanetti A, Marai M, Chen J, et al. Asymmetric synthesis and biological evaluation of imidazole- and oxazole-containing synthetic lipoxin A4 mimetics (sLXms). Eur J Med Chem. 2019; 162: 80-108. doi: 10.1016/j.ejmech.2018.10.049

23. Rao Z, Caprioglio D, Gollowitzer A, Kretzer C, Imperio D, Collado JA, et al. Rotational constriction of curcuminoids impacts 5-lipoxygenase and mPGES-1 inhibition and evokes a lipid mediator class switch in macrophages. Biochem Pharmacol. 2022; 203: 115202. doi: 10.1016/j.bcp.2022.115202

24. Werner M, Jordan PM, Romp E, Czapka A, Rao Z, Kretzer C, et al. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome. FASEB J. 2019; 33(5): 6140- 6153. doi: 10.1096/fj.201802509R

25. Han YH, Lee K, Saha A, Han J, Choi H, Noh M, et al. Specialized proresolving mediators for therapeutic interventions targeting metabolic and inflammatory disorders. Biomol Ther (Seoul). 2021; 29(5): 455-464. doi: 10.4062/biomolther

26. Perretti M, Godson C. Formyl peptide receptor type 2 agonists to kick-start resolution pharmacology. Br J Pharmacol. 2020; 177(20): 4595-600. doi: 10.1111/bph.15212

27. Avilla MN, Malecki KMC, Hahn ME, Wilson RH, Bradfield CA. The Ah receptor: Adaptive metabolism, ligand diversity, and the xenokine model. Chem Res Toxicol. 2020; 33: 860-879. doi: 10.1021/acs.chemrestox.9b00476

28. Larigot L, Benoit L, Koual M, Tomkiewicz C, Barouki R, Coumoul X. Aryl hydrocarbon receptor and its diverse ligands and functions: An exposome receptor. Annu Rev Pharmacol Toxicol. 2022; 62: 383-404. doi: 10.1146/annurev-pharmtox-052220-115707

29. Bock KW. Aryl hydrocarbon receptor (AHR)-mediated inflammation and resolution: Non-genomic and genomic signaling. Biochem Pharmacol. 2020; 182: 114220. doi: 10.1016/j.bcp.2020.114220

30. Samuelsson B. From studies of biochemical mechanism to novel biological mediators: Prostaglandin endoperoxides, thromboxanes, and leukotrienes. Nobel Lecture, 1982. Biosci Rep. 1983; 3(9): 791-813. doi: 10.1007/BF01133779

31. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971; 231(25): 232-235. doi: 10.1038/newbio231232a0

32. Houck JC. Chemical messengers of the inflammatory process. Amsterdam: Elsevier/North-Holland Biomedical Press; 1979. 33. Weissmann G, Smolen JE, Korchak HM. Release of inflammatory mediators from stimulated neutrophils. N Engl J Med. 1980; 303(1): 27-34. doi: 10.1056/NEJM198007033030109

33. Cotran RS, Kumar V, Robbins SL, Schoen FJ. Robbins pathologic basis of disease; 5th ed. Philadelphia: W.B. Saunders; 1994.

34. Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation: Signals in resolution. Nat Immunol. 2001; 2(7): 612-619. doi: 10.1038/89759

35. Serhan CN. Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis: An update and role in anti-inflammation and proresolution. Prostaglandins Other Lipid Mediat. 2002; 68-69: 433-455. doi: 10.1016/s0090-6980(02)00047-3

36. Derada Troletti C, Enzmann G, Chiurchiù V, Kamermans A, Tietz SM, Norris PC, et al. Pro-resolving lipid mediator lipoxin A(4) attenuates neuro-inflammation by modulating T cell responses and modifies the spinal cord lipidome. Cell Rep. 2021; 35(9): 109201. doi: 10.1016/j.celrep.2021.109201

37. Boff D, Oliveira VLS, Queiroz Junior CM, Galvão I, Batista NV, Gouwy M. Lipoxin A(4) impairs effective bacterial control and potentiates joint inflammation and damage caused by Staphylococcus aureus infection. FASEB J. 2020; 34(9): 11498-11510. doi: 10.1096/fj.201802830RR

38. Lecomte M, Laneuville O, Ji C, DeWitt DL, Smith WL. Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin. J Biol Chem. 1994; 269(18): 13207- 13215.

39. Chiang N, Serhan CN. Specialized pro-resolving mediator network: An update on production and actions. Essays Biochem. 2020; 64: 443-462. doi: 10.1042/EBC20200018

40. Werz O. Introduction to the lipid mediators special issue. Biochem Pharmacol. 2023; 207: 115375. doi: 10.1016/j.bcp.2022.115375

41. Schebb NH, Kühn H, Kahnt AS, Rund KM, O’Donnell VB, Flamand N, et al. Formation, signaling and occurrence of specialized pro-resolving lipid mediators – What is the evidence so far? Front Pharmacol. 2022; 13: 838782. doi: 10.3389/fphar.2022.838782

42. Birnbaum Y, Ye Y, Lin Y, Freeberg SY, Nishi SP, Martinez JD, et al. Augmentation of myocardial production of 15-epi-lipoxin-a4 by pioglitazone and atorvastatin in the rat. Circulation. 2006; 114(9): 929-935. doi: 10.1161/CIRCULATIONAHA.106.629907

43. Planagumà A, Pfeffer MA, Rubin G, Croze R, Uddin M, Serhan CN, et al. Lovastatin decreases acute mucosal inflammation via 15-epi-lipoxin A4. Mucosal Immunol. 2010; 3(3): 270-279. doi: 10.1038/mi.2009.141

44. Biringer RG. The enzymology of human eicosanoid pathways: The lipoxygenase branches. Mol Biol Rep. 2020; 47(9); 7189-7207. doi: 10.1007/s11033-020-05698-8

45. Kulkarni JL, Nadler RG, Mirmira I. Regulation of tissue inflammation by 12-lipoxygenases. Biomolecules. 2021; 11(5): 717. doi: 10.3390/biom11050717

46. Romano M. Lipoxin and aspirin-triggered lipoxins. Sci World J. 2010; 10: 1048-1064. doi: 10.1100/tsw.2010.113

47. Claria J, Serhan CN. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc Natl Acad Sci U S A. 1995; 92: 9475-9479. doi: 10.1073/pnas.92.21.9475

48. Green AR, Freedman C, Tena J, Tourdot BE, Liu B, Holinstat M, et al. 5S,15S-dihydroperoxyeicosatetraenoic acid (5,15-diHpETE) as a lipoxin intermediate: Reactivity and kinetics with human leukocyte 5-lipoxygenase, platelet 12-lipoxygenase, and reticulocyte 15-lipoxygenase-1. Biochemistry. 2018; 57(48): 6726-6734. doi: 10.1021/acs.biochem.8b00889

49. Mainka M, George S, Angioni C, Ebert R, Goebel T, Kampschulte N, et al. On the biosynthesis of specialized pro-resolving mediators in human neutrophils and the influence of cell integrity. Biochim Biophys Acta Mol Cell Biol Lipids. 2022; 1867(3) :159093. doi: 10.1016/j.bbalip.2021.159093

50. Rådmark O. Formation of eicosanoids and other oxylipins in human macrophages. Biochem Pharmacol. 2022; 204: 115210. doi: 10.1016/j.bcp.2022.115210

51. Dalli J, Serhan CN. Specific lipid mediator signatures of human phagocytes: Microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood. 2012; 120(15): e60-e72. doi: 10.1182/blood-2012-04-423525

52. Tylek K, Trojan E, Leśkiewicz M, Regulska M, Bryniarska N, Curzytek K, et al. Time-dependent protective and pro-resolving effects of FPR2 agonists on lipopolysaccharide-exposed microglia cells involve inhibition of NF-κB and MAPKs pathways. Cells. 2021; 10(9): 2373. doi: 10.3390/cells10092373

53. Barnig C, Frossard N, Levy BD. Towards targeting resolution pathways of airway inflammation in asthma. Pharmacol Ther. 2018; 186: 98-113. doi: 10.1016/j.pharmthera.2018.01.004

54. Ho CF, Ismail NB, Koh JK, Gunaseelan S, Low YH, Ng YK, et al. Localisation of formyl-peptide receptor 2 in the rat central nervous system and its role in axonal and dendritic outgrowth. Neurochem Res. 2018; 43(8): 1587-1598. doi: 10.1007/s11064-018-2573-0

55. Filep JG, Sekheri M, Kebir DE. Targeting formyl peptide receptors to facilitate the resolution of inflammation. Eur J Pharmacol. 2018; 833: 339-348. doi: 10.1016/j.ejphar.2018.06.025

56. Chen T, Xiong M, Zong X, Ge Y, Zhang H, Wang M, et al. Structural basis of ligand binding modes at the human formyl peptide receptor 2. Nat Commun. 2020; 11(1): 1208. doi: 10.1038/s41467-020-15009-1

57. McArthur S, Juban G, Gobbetti T, Desgeorges T, Theret M, Gondin J, et al. Annexin A1 drives macrophage skewing to accelerate muscle regeneration through AMPK activation. J Clin Invest. 2020; 130(3): 1156-1167. doi: 10.1172/JCI124635

58. Qin CX, Norling LV, Vecchio EA, Brennan EP, May LT, Wootten D, et al. Formylpeptide receptor 2: Nomenclature, structure, signalling and translational perspectives: IUPHAR review 35. Br J Pharmacol. 2022; 179(19): 4617-4639. doi: 10.1111/bph.15919

59. Merlin J, Park J, Vandekolk TH, Fabb SA, Allinne J, Summers RJ, et al. Multipathway in vitro pharmacological characterization of specialized proresolving G protein-coupled receptors. Mol Pharmacol. 2022; 101(4): 246-256. doi: 10.1124/molpharm.121.000422

60. Quintana FJ. Regulation of central nervous system autoimmunity by the aryl hydrocarbon receptor. Semin Immunopathol. 2013; 35: 627-635. doi: 10.1007/s00281-013-0397-1

61. Stockinger B, Di Meglio P, Gialitakis M, Duarte JH. The aryl hydrocarbon receptor: Multitasking in the immune system. Annu Rev Immunol. 2014; 32: 403-432. doi: 10.1146/annurev-immunol-032713-120245

62. Tsai MJ, Hsu YL, Wang TN, Wu LY, Lien CT, Hung CH, et al. Aryl hydrocarbon receptor (AhR) agonists increase airway epithelial matrix metalloproteinase activity. J Mol Med (Berl). 2014; 92(6): 615-628. doi: 10.1007/s00109-014-1121-x

63. Chiba T, Uchi H, Yasukawa F, Furue M. Role of the arylhydrocarbon receptor in lung disease. Int Arch Allergy Immuno. 2021; l(155): 129-134. doi: 10.1159/000327499

64. Körner A, Zhou E, Müller C, Mohammed Y, Herceg S, Bracher F, et al. Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution. Proc Natl Acad Sci U S A. 2019; 116(41): 20623-20634. doi: 10.1073/pnas.1911992116

65. Corminboeuf O, Leroy X. FPR2/ALXR agonists and the resolution of inflammation. J Med Chem. 2015; 58(2): 537-559. doi: 10.1021/jm501051x

66. Godson C, Guiry P, Brennan E. Lipoxin mimetics and the resolution of inflammation. Annu Rev Pharmacol Toxicol. 2023; 63: 429-448. doi: 10.1146/annurev-pharmtox-051921-085407

67. Kong X, Wu SH, Zhang L, Chen XQ. Pilot application of lipoxin A4 analog and lipoxin A4 receptor agonist in asthmatic children with acute episodes. Exp Ther Med. 2017; 14(3): 2284-2290. doi: 10.3892/etm.2017.4787

68. Lind S, Sundqvist M, Holmdahl R, Dahlgren C, Forsman H, Olofsson P. Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949. Biochem Pharmacol. 2019; 166: 163-173. doi: 10.1016/j.bcp.2019.04.030

69. Wang H, Do DC, Liu J, Wang B, Qu J, Ke X, et al. Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2018; 141(2): 586-600.e6. doi: 10.1016/j.jaci.2017.06.013

70. Weng CM, Wang CH, Lee MJ, He JR, Huang HY, Chao MW, et al. Aryl hydrocarbon receptor activation by diesel exhaust particles mediates epithelium-derived cytokines expression in severe allergic asthma. Allergy. 2018; 73(11): 2192-2204. doi: 10.1111/all.13462

71. Wang E, Liu X, Tu W, Do DC, Yu H, Yang L, et al. Benzo(a) pyrene facilitates dermatophagoides group 1 (Der f 1)-induced epithelial cytokine release through aryl hydrocarbon receptor in asthma. Allergy. 2019; 74(9): 1675-1690. doi: 10.1111/all.13784

72. Shivanna B, Chu C, Welty SE, Jiang W, Wang L, Couroucli XI, et al. Omeprazole attenuates hyperoxic injury in H441 cells via the aryl hydrocarbon receptor. Free Radic Biol Med. 2011; 51(10): 1910-1917. doi: 10.1016/j.freeradbiomed.2011.08.013

73. Shivanna B, Chu C, Moorthy B. The aryl hydrocarbon receptor (AHR): A novel therapeutic target for pulmonary diseases? Int J Mol Sci. 2022; 23(3): 1516. doi: 10.3390/ijms23031516

74. Yagoubi A, Laid Y, Smati L, Nafissa Benhalla K, Benhassine F. Does omeprazole improve asthma-control in poorly-controlled asthmatic children with gastro-esophageal reflux. J Asthma. 2022; 59(6): 1169-1176. doi: 10.1080/02770903.2021.1917606

75. Wang WT, Li CY, Chang YT, Bai YM, Tsai SJ, Chen TJ, et al. Proton-pump inhibitors are associated with an increased risk of asthma: A nationwide nested case-control study. Allergy Asthma Proc. 2023; 44(5): 345-353. doi: 10.2500/aap.2023.44.230035

76. Safe S, Jin UH, Park H, Chapkin RS, Jayaraman A. Aryl hydrocarbon receptor (AHR) ligands as selective AHR modulators (SAhRMs). Int J Mol Sci. 2020; 21(18): 6654. doi: 10.3390/ijms21186654

77. Levy BD, Bonnans C, Silverman ES, Palmer LJ, Marigowda G, Israel E, et al. Diminished lipoxin biosynthesis in severe asthma. Am J Respir Crit Care Med. 2005; 172(7): 824-830. doi: 10.1164/rccm.200410-1413OC

78. Tattersfield AE, Knox AJ, Britton JR, Hall IP. Asthma. Lancet. 2002; 360: 1313-1322. doi: 10.1016/s0140-6736(02)11312-2

79. Yamaguchi H, Higashi N, Mita H, Ono E, Komase Y, Nakagawa T, et al. Urinary concentrations of 15-epimer of lipoxin A(4) are lower in patients with aspirin-intolerant compared with aspirin-tolerant asthma. Clin Exp Allergy. 2011; 41(12): 1711-1718. doi: 10.1111/j.1365-2222.2011.03839.x