Lubov A. Ponomareva , Igor S. Zubarev , Svetlana A. Berns , Alina A. Chinova , Elena N. Popova
Abstract
N-acetylcysteine (Fluimucil) is characterized by high antioxidant potential due to direct effect on both free radicals through inhibition of free radical reactions, including those related to the mechanisms underlying the iron-dependent cell death (ferroptosis), and the synthesis of the antioxidant molecules constituting the antioxidant protection system. The review is focused on the N-acetylcysteine involvement in the development of antioxidant protection and on the use of high doses of N-acetylcysteine in combination with thiamphenicol for treatment of bacterial infections.
Keywords: respiratory epithelium, inflammatory pulmonary diseases, bacterial infections, N-acetylcysteine.
Keywords: respiratory epithelium, inflammatory pulmonary diseases, bacterial infections, N-acetylcysteine.
About the Author
Lubov A. Ponomareva 1 , Igor S. Zubarev 2 , Svetlana A. Berns 2 , Alina A. Chinova 3 , Elena N. Popova 11 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
2 National Medical Research Center for Therapy and Preventive Medicine, Moscow, Russia
3 City Clinical Hospital No. 52, Moscow, Russia
References
1. Pawankar R, Canonica GW, Holgate ST, Lockey RF. Allergic diseases and asthma: a major global health concern. Curr Opin Allergy Clin Immunol 2012;12(1):39-41. DOI: 10.1097/ACI.0b013e32834ec13b. PMID: 22157151.
2. Lozano R, Naghavi M, Foreman K et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380(9859):2095-128. DOI: 10.1016/S0140-6736(12)61728-0. Erratum in: Lancet. 2013 Feb 23;381(9867):628.
3. Li X, Cao X, Guo M et al. Trends and risk factors of mortality and disability adjusted life years for chronic respiratory diseases from 1990 to 2017: systematic analysis for the Global Burden of Disease Study 2017. BMJ 2020;368:m234. DOI: 10.1136/bmj.m234. Erratum in: BMJ 2020;370:m3150. DOI: 10.1136/bmj.m3150. PMID: 32075787; PMCID: PMC7190065.
4. Abohalaka R. Bronchial epithelial and airway smooth muscle cell interactions in health and disease. Heliyon 2023;9(9):19976. DOI: 10.1016/j.heliyon.2023.e19976
5. Yan F. Roles of airway smooth muscle dysfunction in chronic obstructive pulmonary disease. J Transl Med 2018;(16):262.
6. Tankut G et al. Epithelial-stromal cell interactions and extracellular matrix mechanics drive the formation of airway-mimetic tubular morphology in lung organoids. iScience 2021;24(9):103061.
7. Humayun M, Chow CW, Young EWK. Microfluidic lung airway-on-a-chip with arrayable suspended gels for studying epithelial and smooth muscle cell interactions. Lab Chip 2018;18(9):1298-309. DOI: 10.1039/c7lc01357d. PMID: 29651473.
8. Burgoyne RA, Fisher AJ, Borthwick LA. The Role of Epithelial Damage in the Pulmonary Immune Response. Cells 2021;10(10):2763. DOI: 10.3390/cells10102763. PMID: 34685744; PMCID: PMC8534416.
9. Carmo-Fernandes A, Puschkarow M, Peters K et al. The Pathogenic Role of Smooth Muscle Cell-Derived Wnt5a in a Murine Model of Lung Fibrosis. Pharmaceuticals 2021;14(8):755.
10. Sauleda J, Núñez B, Sala E, Soriano JB. Idiopathic Pulmonary Fibrosis: Epidemiology, Natural History, Phenotypes. Med Sci (Basel) 2018;6(4):110. DOI: 10.3390/medsci6040110. PMID: 30501130; PMCID: PMC6313500.
11. Fain SB, Altes TA, Panth SR et al. Detection of age-dependent changes in healthy adult lungs with diffusion-weighted 3He MRI. Acad Radiol 2005;12:1385-93.
12. Godin LM, Sandri BJ, Wagner DE et al. Decreased Laminin Expression by Human Lung Epithelial Cells and Fibroblasts Cultured in Acellular Lung Scaffolds from Aged Mice. PLoS ONE 2016;(11):e0150966.
13. Schneider JL, Rowe JH, Garcia-de-Alba C et al. The aging lung: Physiology, disease, and immunity. Cell 2021;184(8):1990-2019. DOI: 10.1016/j.cell.2021.03.005. Epub 2021 Apr 2. PMID: 33811810; PMCID: PMC8052295.
14. Ascher K, Elliot SJ, Rubio GA, Glassberg MK. Lung Diseases of the Elderly: Cellular Mechanisms. Clin Geriatr Med 2017;33(4):473-90. DOI: 10.1016/j.cger.2017.07.001. Epub 2017 Aug 18. PMID: 28991645.
15. Carter P, Lagan J, Fortune C et al. Association of Cardiovascular Disease With Respiratory Disease. J Am Coll Cardiol 2019;73(17):2166-77. DOI: 10.1016/j.jacc.2018.11.063
16. Shen L, Jhund PS, Anand IS et al. Incidence and Outcomes of Pneumonia in Patients With Heart Failure. J Am Coll Cardiol 2021;77(16):1961-73. DOI: 10.1016/j.jacc.2021.03.001
17. Forman HJ, Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov 2021;20(9):689-709. DOI: 10.1038/s41573-021-00233-1. Epub 2021 Jun 30. Erratum in: Nat Rev Drug Discov 2021;20(8):652. DOI: 10.1038/s41573-021-00267-5. PMID: 34194012; PMCID: PMC8243062.
18. Beavers WN, Skaar EP. Neutrophil-generated oxidative stress and protein damage in Staphylococcus aureus. Pathog Dis 2016;74(6):ftw060. DOI: 10.1093/femspd/ftw060. Epub 2016 Jun 27. PMID: 27354296; PMCID: PMC5975594.
19. Sathe N, Beech P, Croft L et al. Pseudomonas aeruginosa: Infections and novel approaches to treatment «Knowing the enemy» the threat of Pseudomonas aeruginosa and exploring novel approaches to treatment. Infect Med (Beijing) 2023;2(3):178-94. DOI: 10.1016/j.imj. 2023.05.003
20. Qin S, Xiao W, Zhou C et al. Pseudomonas aeruginosa: pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics. Signal Transduct Target Ther 2022;7(1):199. DOI:10.1038/s41392-022-01056-1
21. Dailah HG. Therapeutic Potential of Small Molecules Targeting Oxidative Stress in the Treatment of Chronic Obstructive Pulmonary Disease (COPD): A Comprehensive Review. Molecules 2022;27(17):5542. DOI: 10.3390/molecules27175542. PMID: 36080309; PMCID: PMC9458015.
22. Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. Sci World J 2013;(2013):16. DOI: 10.1155/2013/162750. 162750
23. Gould NS, Day BJ. Targeting maladaptive glutathione responses in lung disease. Biochem Pharmacol 2011;81(2):187-93. DOI: 10.1016/ j.bcp.2010.10.001
24. Ghezzi P. Protein glutathionylation in health and disease. Biochim Biophys Acta 2013;1830(5):3165-72. DOI: 10.1016/j.bbagen.2013.02.009
25. Santus P, Signorello JC, Danzo F et al. Anti-Inflammatory and Anti-Oxidant Properties of N-Acetylcysteine: A Fresh Perspective. J Clin Med 2024;(13):4127. DOI: 10.3390/jcm13144127
26. Moldéus P, Cotgreave IA, Berggren M. Lung protection by a thiol-containing antioxidant: N-acetylcysteine. Respiration 1986;50(Suppl.1): 31-42. DOI: 10.1159/000195086
27. Tenório MCDS, Graciliano NG, Moura FA et al. N-Acetylcysteine (NAC): Impacts on Human Health. Antioxidants (Basel) 2021;10(6): 967. DOI: 10.3390/antiox10060967
28. Santus P, Corsico A, Solidoro P et al. Oxidative stress and respiratory system: pharmacological and clinical reappraisal of N-acetylcysteine. COPD 2014;11(6):705-17. DOI: 10.3109/15412555.2014.898040
29. Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 2014;141(2):150-9. DOI: 10.1016/j.pharmthera.2013.09.006. Epub 2013 Sep 28.
30. Zhao T, Liu Y. N-acetylcysteine inhibit biofilms produced by Pseudomonas aeruginosa. BMC Microbiol 2010;(10):140. DOI: 10.1186/1471-2180-10-140
31. Izquierdo JL, Soriano JB, González Y et al. Use of N-Acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19. Sci Prog 2022;105(1):368504221074574. DOI: 10.1177/0036850422107 4574. PMID: 35084258; PMCID: PMC8795755.
32. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021;22(4):266-82. DOI: 10.1038/s41580-020-00324-8. Epub 2021 Jan 25.
33. Dar HH, Anthonymuthu TS, Ponomareva LA et al. A new thiol-independent mechanism of epithelial host defense against Pseudomonas aeruginosa: iNOS/NO – sabotage of theft-ferroptosis. Redox Biol 2021;45:102045. DOI: 10.1016/j.redox.2021.102045. Epub 2021 Jun 16. PMID: 34167028; PMCID: PMC8227829.
34. Kapralov AA, Yang Q, Dar HH et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat Chem Biol 2020;16(3):278-90. DOI: 10.1038/s41589-019-0462-8. Epub 2020 Feb 17. PMID: 32080625; PMCID: PMC7233108
35. Del Pozo JL. Biofilm-related disease. Expert Rev Anti Infect Ther 2018;16(1):51-65. DOI: 10.1080/14787210.2018.1417036. Epub 2017 Dec 19.
36. Blasi F, Page C, Rossolini GM et al. The effect of N-acetylcysteine on biofilms: Implications for the treatment of respiratory tract infections. Respir Med 2016;(117):190-7. DOI: 10.1016/j.rmed.2016.06.015. Epub 2016 Jun 16.
37. Vance RE, Hong S, Gronert K et al. The opportunistic pathogen Pseudomonas aeruginosa carries a secretable arachidonate 15-lipoxygenase. Proc Natl Acad Sci U S A 2004;101(7):2135-9. DOI: 10.1073/pnas. 0307308101. Epub 2004 Feb 6.
38. Dar HH, Epperly MW, Tyurin VA et al. P. aeruginosa augments irradiation injury via 15-lipoxygenase-catalyzed generation of 15-HpETE-PE and induction of theft-ferroptosis. JCI Insight 2022;7(4):e156013. DOI: 10.1172/jci.insight.156013
39. Иванчик Н.В., Сухорукова М.В., Чагарян А.Н. и др. In vitro активность тиамфеникола в отношении клинических изолятов Haemophilus influenzae, Streptococcus pneumoniae и Streptococcus pyogenes. Клиническая микробиология и антимикробная химиотерапия. 2021;23(1):92-9.
Ivanchik N.V., Sukhorukova M.V., Chagaryan A.N., et al. In vitro activity of thiamphenicol against clinical isolates of Haemophilus influenzae, Streptococcus pneumoniae, and Streptococcus pyogenes. Clinical Microbiology and Antimicrobial Chemotherapy. 2021;23(1):92-9 (in Russian).
40. Drago L, Fassina MC, Mombelli B et al. Comparative effect of thiamphenicol glycinate, thiamphenicol glycinate N-acetylcysteinate, amoxicillin plus clavulanic acid, ceftriaxone and clarithromycin on pulmonary clearance of Haemophilus influenzae in an animal model. Chemotherapy 2000;46(4):275-81. DOI: 10.1159/000007299
41. Постников С.С., Грацианская А.Н. Ингаляционная терапия при респираторных инфекциях: Флуимуцил антибиотик ИТ. Практика педиатра. 2016;(3):56-9.
Postnikov S.S., Gratsianskaya A.N. Inhalation therapy for respiratory infections: Fluimucil antibiotic IT. Pediatrician Practice 2016;3:56-9 (in Russian).
42. Brandenberger C, Mühlfeld C. Mechanisms of lung aging. Cell Tissue Res 2017;367(3):469-80. DOI: 10.1007/s00441-016-2511-x. Epub 2016 Oct 14. PMID: 27743206.
For citation:Ponomareva L.A., Zubarev I.S., Berns S.A., Chinova A.A., Popova E.N. Modern respiratory epithelium protection mechanisms. Clinical review for general practice. 2024; 5 (11): 76–82 (In Russ.). DOI: 10.47407/kr2024.5.11.00520
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