Evaluation of Leucomethylene Blue as a Protective Agent Against Acetaminophen-Induced Acute Lung Injury
-
Majid efati
,
Sahar Ghoflchi
,
Khatereh Kharazmi
,
Soodeh Alidadi
,
Daryoush Hamidi-alamdari
,
Hossein Hosseini
Abstract
Objectives: Acetaminophen overdose may lead to acute pulmonary complications like acute lung injury because of its overdose harmful effect on cellular systems due to oxidative stress. leucomethylene blue (LMB) may have beneficial effects by improving hemodynamic stability and reducing oxidative damage through its nitric oxide synthase inhibitory and antioxidant activities. This study aimed to evaluate the effect of LMB on acetaminophen-induced pulmonary injury in rats.
Methods: Lung samples were collected from 30 male Wistar rats, which were randomly split into five groups, and frozen for later analysis. The groups included control, acetaminophen, N-acetylcysteine (NAC) treated, LMB treated, and NAC+LMB combination treated. We evaluated total antioxidant capacity (TAC), glutathione reductase (GR), TNF-α and IL-6 levels, histopathology, and relevant tissue remodeling changes.
Results: Our results demonstrated that the administration of LMB greatly diminished the oxidative and inflammatory damage caused by APAP toxicity in the lungs. LMB restored TAC and GR activity that were significantly depressed by APAP toxicity. Additionally, LMB restricted the overproduction of pro-inflammatory cytokines that were released from lung tissue. Moreover, LMB substantially counteracted the pulmonary lesions caused by APAP, including edema, hemorrhage, and inflamed cells, corroborated by histopathological analysis.
Conclusion: The results of this study showed that LMB can effectively reduce lung damage caused by acetaminophen poisoning.
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11. Sabbahi S, Alouini Z, Jemli M, Boudabbous A. The role of reactive oxygen species in Staphylococcus aureus photoinactivation by methylene blue. Water Sci Technol. 2008;58(5):1047-54. https://doi.org/10.2166/wst.2008.471
12. Lee JH, Chang CH, Park CH, Kim JK. Methylene blue dye-induced skin necrosis in immediate breast reconstruction: evaluation and management. Arch Plast Surg. 2014;41(3):258-63. https://doi.org/10.5999/aps.2014.41.3.258
13. Oz M, Lorke DE, Hasan M, Petroianu GA. Cellular and molecular actions of Methylene Blue in the nervous system. Med Res Rev. 2011;31(1):93-117. https://doi.org/10.1002/med.20177
14. Ou G, Che J, Dong J, Deng Y, Jiang X, Sun Y, et al. Methylene blue targets PHD3 expression in murine microglia to mitigate lipopolysaccharide-induced neuroinflammation and neurocognitive impairments. Int Immunopharmacol. 2023;120:110349. https://doi.org/10.1016/j.intimp.2023.110349
15. Tian WF, Zeng S, Sheng Q, Chen JL, Weng P, Zhang XT, et al. Methylene Blue Protects the Isolated Rat Lungs from Ischemia-Reperfusion Injury by Attenuating Mitochondrial Oxidative Damage. Lung. 2018;196(1):73-82. https://doi.org/10.1007/s00408-017-0072-8
16. Efati M, Sahebkar A, Tavallaei S, Alidadi S, Hosseini H, Hamidi-Alamdari D. Protective effect of Leuco-methylene blue against acetaminophen-induced liver injury: an experimental study. Drug Chem Toxicol. 2025:1-13. https://doi.org/10.1080/01480545.2025.2485347
17. Xavier MS, Vane MF, Vieira RF, Oliveira CC, Maia DR, de Castro LU, et al. Methylene blue as an adjuvant during cardiopulmonary resuscitation: an experimental study in rats. Braz J Anesthesiol. 2024;74(2):744470. https://doi.org/10.1016/j.bjane.2023.10.003
18. Dobrinskikh E, Al-Juboori SI, Zarate MA, Zheng L, De Dios R, Balasubramaniyan D, et al. Pulmonary implications of acetaminophen exposures independent of hepatic toxicity. Am J Physiol Lung Cell Mol Physiol. 2021;321(5):L941-l53. https://doi.org/10.1152/ajplung.00234.2021
19. Sandoval J, Orlicky DJ, Allawzi A, Butler B, Ju C, Phan CT, et al. Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung. Oxid Med Cell Longev. 2019;2019(1):7595126. https://doi.org/https://doi.org/10.1155/2019/7595126
20. McKeever TM, Lewis SA, Smit HA, Burney P, Britton JR, Cassano PA. The association of acetaminophen, aspirin, and ibuprofen with respiratory disease and lung function. Am J Respir Crit Care Med. 2005;171(9):966-71. https://doi.org/10.1164/rccm.200409-1269OC
21. Oz M, Lorke DE, Hasan M, Petroianu GA. Cellular and molecular actions of methylene blue in the nervous system. Medicinal research reviews. 2011;31(1):93-117.
22. Tucker D, Lu Y, Zhang Q. From mitochondrial function to neuroprotection—an emerging role for methylene blue. Mol Neurobiol. 2018;55:5137-53. https://doi.org/10.1007/s12035-017-0712-2
23. Gomez-Sequeda N, Jimenez-Del-Rio M, Velez-Pardo C. The Antiproteinopathy, Antioxidant, and Antiapoptotic Effects of Methylene Blue and 4-Phenylbutyric Acid Alone, and in Combination on Familial Alzheimer’s Disease PSEN1 I416T Cholinergic-Like Neurons. ACS Chem Neurosci. 2024;15(19):3563-75. https://doi.org/10.1021/acschemneuro.4c00472
24. Piret B, Legrand-Poels S, Sappey C, Piette J. NF-kappa B transcription factor and human immunodeficiency virus type 1 (HIV-1) activation by methylene blue photosensitization. Eur J Biochem. 1995;228(2):447-55. https://doi.org/10.1111/j.1432-1033.1995.tb20283.x
25. Hodgman MJ, Garrard AR. A review of acetaminophen poisoning. Crit Care Clin. 2012;28(4):499-516. https://doi.org/10.1016/j.ccc.2012.07.006
26. Du K, Ramachandran A, Jaeschke H. Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential. Redox Biol. 2016;10:148-56. https://doi.org/10.1016/j.redox.2016.10.001
27. Ali Akbar S, Behnam Omidi S, Masoume A, Marzyeh A, Reza M. A review of the therapeutic effects of polyphenols on non-alcoholic fatty liver disease: Focus on oxidative stress. Acta Biochimica Iranica. 2024;2(1). https://doi.org/10.18502/abi.v2i1.16242
2. Barr RG, Wentowski CC, Curhan GC, Somers SC, Stampfer MJ, Schwartz J, et al. Prospective study of acetaminophen use and newly diagnosed asthma among women. Am J Respir Crit Care Med. 2004;169(7):836-41. https://doi.org/10.1164/rccm.200304-596oc
3. Shaheen S, Newson R, Sherriff A, Henderson A, Heron J, Burney P, et al. Paracetamol use in pregnancy and wheezing in early childhood. Thorax. 2002;57(11):958-63. https://doi.org/10.1136/thorax.57.11.958
4. Anoush M, Eghbal MA, Fathiazad F, Hamzeiy H, Kouzehkonani NS. The protective effects of garlic extract against acetaminophen-induced oxidative stress and glutathione depletion. Pak J Biol Sci. 2009;12(10):765-71. https://doi.org/10.3923/pjbs.2009.765.771
5. Ozawa M, Kubo T, Lee SH, Oe T. LC-MS analyses of N-acetyl-p-benzoquinone imine-adducts of glutathione, cysteine, N-acetylcysteine, and albumin in a plasma sample: A case study from a patient with a rare acetaminophen-induced acute swelling rash. J Toxicol Sci. 2019;44(8):559-63. https://doi.org/10.2131/jts.44.559
6. Ali Karami R, Zahra S, Mohammad Amin V, Banafsheh S, Farzad Izak S, Masoumeh T-Y. Caffeic acid stimulates breast cancer death through Reactive oxygen species (ROS) formation, Caspase activation and mitochondrial membrane potential depletion. Acta Biochim Iran. 2023;1(4). https://doi.org/10.18502/abi.v1i4.14719
7. Klopčič I, Poberžnik M, Mavri J, Dolenc MS. A quantum chemical study of the reactivity of acetaminophen (paracetamol) toxic metabolite N-acetyl-p-benzoquinone imine with deoxyguanosine and glutathione. Chem Biol Interact. 2015;242:407-14. https://doi.org/10.1016/j.cbi.2015.11.002
8. Yang S, Zhang T, Ge Y, Cheng Y, Yin L, Pu Y, et al. Ferritinophagy Mediated by Oxidative Stress-Driven Mitochondrial Damage Is Involved in the Polystyrene Nanoparticles-Induced Ferroptosis of Lung Injury. ACS Nano. 2023;17(24):24988-5004. https://doi.org/10.1021/acsnano.3c07255
9. Barańska A, Kanadys W, Wdowiak A, Malm M, Błaszczuk A, Religioni U, et al. Effects of Prenatal Paracetamol Exposure on the Development of Asthma and Wheezing in Childhood: A Systematic Review and Meta-Analysis. J Clin Med. 2023;12(5). https://doi.org/10.3390/jcm12051832
10. Shaheen SO, Newson RB, Ring SM, Rose-Zerilli MJ, Holloway JW, Henderson AJ. Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms, and childhood asthma. J Allergy Clin Immunol. 2010;126(6):1141-8.e7. https://doi.org/10.1016/j.jaci.2010.08.047
11. Sabbahi S, Alouini Z, Jemli M, Boudabbous A. The role of reactive oxygen species in Staphylococcus aureus photoinactivation by methylene blue. Water Sci Technol. 2008;58(5):1047-54. https://doi.org/10.2166/wst.2008.471
12. Lee JH, Chang CH, Park CH, Kim JK. Methylene blue dye-induced skin necrosis in immediate breast reconstruction: evaluation and management. Arch Plast Surg. 2014;41(3):258-63. https://doi.org/10.5999/aps.2014.41.3.258
13. Oz M, Lorke DE, Hasan M, Petroianu GA. Cellular and molecular actions of Methylene Blue in the nervous system. Med Res Rev. 2011;31(1):93-117. https://doi.org/10.1002/med.20177
14. Ou G, Che J, Dong J, Deng Y, Jiang X, Sun Y, et al. Methylene blue targets PHD3 expression in murine microglia to mitigate lipopolysaccharide-induced neuroinflammation and neurocognitive impairments. Int Immunopharmacol. 2023;120:110349. https://doi.org/10.1016/j.intimp.2023.110349
15. Tian WF, Zeng S, Sheng Q, Chen JL, Weng P, Zhang XT, et al. Methylene Blue Protects the Isolated Rat Lungs from Ischemia-Reperfusion Injury by Attenuating Mitochondrial Oxidative Damage. Lung. 2018;196(1):73-82. https://doi.org/10.1007/s00408-017-0072-8
16. Efati M, Sahebkar A, Tavallaei S, Alidadi S, Hosseini H, Hamidi-Alamdari D. Protective effect of Leuco-methylene blue against acetaminophen-induced liver injury: an experimental study. Drug Chem Toxicol. 2025:1-13. https://doi.org/10.1080/01480545.2025.2485347
17. Xavier MS, Vane MF, Vieira RF, Oliveira CC, Maia DR, de Castro LU, et al. Methylene blue as an adjuvant during cardiopulmonary resuscitation: an experimental study in rats. Braz J Anesthesiol. 2024;74(2):744470. https://doi.org/10.1016/j.bjane.2023.10.003
18. Dobrinskikh E, Al-Juboori SI, Zarate MA, Zheng L, De Dios R, Balasubramaniyan D, et al. Pulmonary implications of acetaminophen exposures independent of hepatic toxicity. Am J Physiol Lung Cell Mol Physiol. 2021;321(5):L941-l53. https://doi.org/10.1152/ajplung.00234.2021
19. Sandoval J, Orlicky DJ, Allawzi A, Butler B, Ju C, Phan CT, et al. Toxic Acetaminophen Exposure Induces Distal Lung ER Stress, Proinflammatory Signaling, and Emphysematous Changes in the Adult Murine Lung. Oxid Med Cell Longev. 2019;2019(1):7595126. https://doi.org/https://doi.org/10.1155/2019/7595126
20. McKeever TM, Lewis SA, Smit HA, Burney P, Britton JR, Cassano PA. The association of acetaminophen, aspirin, and ibuprofen with respiratory disease and lung function. Am J Respir Crit Care Med. 2005;171(9):966-71. https://doi.org/10.1164/rccm.200409-1269OC
21. Oz M, Lorke DE, Hasan M, Petroianu GA. Cellular and molecular actions of methylene blue in the nervous system. Medicinal research reviews. 2011;31(1):93-117.
22. Tucker D, Lu Y, Zhang Q. From mitochondrial function to neuroprotection—an emerging role for methylene blue. Mol Neurobiol. 2018;55:5137-53. https://doi.org/10.1007/s12035-017-0712-2
23. Gomez-Sequeda N, Jimenez-Del-Rio M, Velez-Pardo C. The Antiproteinopathy, Antioxidant, and Antiapoptotic Effects of Methylene Blue and 4-Phenylbutyric Acid Alone, and in Combination on Familial Alzheimer’s Disease PSEN1 I416T Cholinergic-Like Neurons. ACS Chem Neurosci. 2024;15(19):3563-75. https://doi.org/10.1021/acschemneuro.4c00472
24. Piret B, Legrand-Poels S, Sappey C, Piette J. NF-kappa B transcription factor and human immunodeficiency virus type 1 (HIV-1) activation by methylene blue photosensitization. Eur J Biochem. 1995;228(2):447-55. https://doi.org/10.1111/j.1432-1033.1995.tb20283.x
25. Hodgman MJ, Garrard AR. A review of acetaminophen poisoning. Crit Care Clin. 2012;28(4):499-516. https://doi.org/10.1016/j.ccc.2012.07.006
26. Du K, Ramachandran A, Jaeschke H. Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential. Redox Biol. 2016;10:148-56. https://doi.org/10.1016/j.redox.2016.10.001
27. Ali Akbar S, Behnam Omidi S, Masoume A, Marzyeh A, Reza M. A review of the therapeutic effects of polyphenols on non-alcoholic fatty liver disease: Focus on oxidative stress. Acta Biochimica Iranica. 2024;2(1). https://doi.org/10.18502/abi.v2i1.16242
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| Issue | Vol 3 No 2 (2025) | |
| Section | Original Articles | |
| Keywords | ||
| LeucoMethylene Blue lung injury Acetaminophen Inflammation Oxidative stress | ||
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How to Cite
1.
efati M, Ghoflchi S, Kharazmi K, Alidadi S, Hamidi-alamdari D, Hosseini H. Evaluation of Leucomethylene Blue as a Protective Agent Against Acetaminophen-Induced Acute Lung Injury. ABI. 2025;3(2):114-119.
