Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Short-term inhalation exposure to cigarette smoke induces oxidative stress and inflammation in lungs without systemic oxidative stress in mice

  • Yoon-Seok Seo (College of Pharmacy, BK21 FOUR Team and Integrated Research Institute for Drug Development, Dongguk University) ;
  • Kwang-Hoon Park (College of Pharmacy, BK21 FOUR Team and Integrated Research Institute for Drug Development, Dongguk University) ;
  • Jung-Min Park (College of Pharmacy, BK21 FOUR Team and Integrated Research Institute for Drug Development, Dongguk University) ;
  • Hyuneui Jeong (Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University) ;
  • Bumseok Kim (Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University) ;
  • Jang Su Jeon (College of Pharmacy, Chungnam National University) ;
  • Jieun Yu (College of Pharmacy, Chungnam National University) ;
  • Sang Kyum Kim (College of Pharmacy, Chungnam National University) ;
  • Kyuhong Lee (Inhalation Toxicology Center for Airborne Risk Factor, Korea Institute of Toxicology) ;
  • Moo-Yeol Lee (College of Pharmacy, BK21 FOUR Team and Integrated Research Institute for Drug Development, Dongguk University)
  • Received : 2023.10.11
  • Accepted : 2023.12.27
  • Published : 2024.04.15
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Abstract

Smoking is a well-established risk factor for various pathologies, including pulmonary diseases, cardiovascular disorders, and cancers. The toxic effects of cigarette smoke (CS) are mediated through multiple pathways and diverse mechanisms. A key pathogenic factor is oxidative stress, primarily induced by excessive formation of reactive oxygen species. However, it remains unclear whether smoking directly induces systemic oxidative stress or if such stress is a secondary consequence. This study aimed to determine whether short-term inhalation exposure to CS induces oxidative stress in extrapulmonary organs in addition to the lung in a murine model. In the experiment, 3R4F reference cigarettes were used to generate CS, and 8-week-old male BALB/c mice were exposed to CS at a total particulate matter concentration of either 0 or 800 ㎍/L for four consecutive days. CS exposure led to an increase in neutrophils, eosinophils, and total cell counts in bronchoalveolar lavage fluid. It also elevated levels of lactate dehydrogenase and malondialdehyde (MDA), markers indicative of tissue damage and oxidative stress, respectively. Conversely, no significant changes were observed in systemic oxidative stress markers such as total oxidant scavenging capacity, MDA, glutathione (GSH), and the GSH/GSSG ratio in blood samples. In line with these findings, CS exposure elevated NADPH oxidase (NOX)-dependent superoxide generation in the lung but not in other organs like the liver, kidney, heart, aorta, and brain. Collectively, our results indicate that short-term exposure to CS induces inflammation and oxidative stress in the lung without significantly affecting oxidative stress in extrapulmonary organs under the current experimental conditions. NOX may play a role in these pulmonary-specific events.

Keywords

Acknowledgement

This research was funded by the Ministry of Food and Drug Safety (21203MFDS318), the National Research Foundation of Korea (2018R1A5A2023127 and 2022R1A2C2007171), and the BK21 FOUR program funded by the Ministry of Education.

References

  1. Seo YS, Park JM, Kim JH, Lee MY (2023) Cigarette smoke-induced reactive oxygen species formation: a concise review. Antioxidants (Basel) 12:1732. https://doi.org/10.3390/antiox12091732
  2. Ambrose JA, Barua RS (2004) The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol 43:1731-1737. https://doi.org/10.1016/j. jacc.2003.12.047
  3. Zuo L, He F, Sergakis GG, Koozehchian MS, Stimpfl JN, Rong Y, Diaz PT, Best TM (2014) Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments. Am J Physiol Lung Cell Mol Physiol 307:L205-L218. https://doi.org/10.1152/ajplung.00330.2013
  4. Barua RS, Ambrose JA (2013) Mechanisms of coronary thrombosis in cigarette smoke exposure. Arterioscler Thromb Vasc Biol 33:1460-1467. https://doi.org/10.1161/ATVBAHA.112.300154
  5. Messner B, Bernhard D (2014) Smoking and cardiovascular disease: mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler Thromb Vasc Biol 34:509-515. https://doi.org/10.1161/ATVBAHA.113.300156
  6. Nagasawa Y, Yamamoto R, Rakugi H, Isaka Y (2012) Cigarette smoking and chronic kidney diseases. Hypertens Res 35:261-265. https://doi.org/10.1038/hr.2011.205
  7. Goldkorn T, Filosto S, Chung S (2014) Lung injury and lung cancer caused by cigarette smoke-induced oxidative stress: Molecular mechanisms and therapeutic opportunities involving the ceramide-generating machinery and epidermal growth factor receptor. Antioxid Redox Signal 21:2149-2174. https://doi.org/10.1089/ars.2013.5469
  8. Pryor WA, Stone K (1993) Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann NY Acad Sci 686:12-27. https://doi.org/10.1111/j.1749-6632.1993.tb39148.x
  9. Pryor WA, Prier DG, Church DF (1983) Electron-spin resonance study of mainstream and sidestream cigarette smoke: nature of the free radicals in gas-phase smoke and in cigarette tar. Environ Health Perspect 47:345-355. https://doi.org/10.1289/ehp.8347345
  10. Wooten JB, Chouchane S, McGrath TE (2006) Tobacco smoke constituents affecting oxidative stress. In: Halliwell BB, Poulsen HE (eds) Cigarette Smoke and Oxidative Stress. Springer, Berlin, Heidelberg, Germany, pp 5-46. https://doi.org/10.1007/3-540-32232-9_2
  11. Abdelghany TM, Ismail RS, Mansoor FA, Zweier JR, Lowe F, Zweier JL (2018) Cigarette smoke constituents cause endothelial nitric oxide synthase dysfunction and uncoupling due to depletion of tetrahydrobiopterin with degradation of GTP cyclohydrolase. Nitric Oxide 76:113-121. https://doi.org/10.1016/j.niox.2018.02.009
  12. Kim M, Han CH, Lee MY (2014) NADPH oxidase and the cardiovascular toxicity associated with smoking. Toxicol Res 30:149-157. https://doi.org/10.5487/TR.2014.30.3.149
  13. Chang KH, Park JM, Lee CH, Kim B, Choi KC, Choi SJ, Lee K, Lee MY (2017) NADPH oxidase (NOX) 1 mediates cigarette smoke-induced superoxide generation in rat vascular smooth muscle cells. Toxicol In Vitro 38:49-58. https://doi.org/10.1016/j.tiv.2016.10.013
  14. Park JM, Jeong H, Seo YS, Do VQ, Choi SJ, Lee K, Choi KC, Choi WJ, Lee MY (2021) Cigarette smoke extract produces superoxide in aqueous media by reacting with bicarbonate. Toxics 9:316. https://doi.org/10.3390/toxics9110316
  15. Morrow JD, Frei B, Longmire AW, Gaziano JM, Lynch SM, Shyr Y, Strauss WE, Oates JA, Roberts LJ Jr (1995) Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage. N Engl J Med 332:1198-1203. https://doi.org/10.1056/NEJM199505043321804
  16. Reilly M, Delanty N, Lawson JA, FitzGerald GA (1996) Modulation of oxidant stress in vivo in chronic cigarette smokers. Circulation 94:19-25. https://doi.org/10.1161/01.cir.94.1.19
  17. Volpe CMO, Villar-Delfino PH, Dos Anjos PMF, NogueiraMachado JA (2018) Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis 9:119. https://doi.org/10.1038/s41419-017-0135-z
  18. Zuo L, Prather ER, Stetskiv M, Garrison DE, Meade JR, Peace TI, Zhou T (2019) Inflammaging and oxidative stress in human diseases: from molecular mechanisms to novel treatments. Int J Mol Sci 20:4472. https://doi.org/10.3390/ijms20184472
  19. Brook RD, Rajagopalan S, Pope CA 3rd, Brook JR, Bhatnagar A, Diez-Roux AV, Holguin F, Hong Y, Luepker RV, Mittleman MA, Peters A, Siscovick D, Smith SC Jr, Whitsel L, Kaufman JD, Council AHA, on E, Prevention CotKiCD, Council on Nutrition PA, Metabolism, (2010) Particulate matter air pollution and cardiovascular disease: An update to the scientific statement from the American Heart Association. Circulation 121:2331-2378. https://doi.org/10.1161/CIR.0b013e3181dbece1
  20. Ma N, Deng TT, Wang Q, Luo ZL, Zhu CF, Qiu JF, Tang XJ, Huang M, Bai J, He ZY, Zhong XN, Li MH (2019) Erythromycin regulates cigarette smoke-induced proinflammatory mediator release through sirtuin 1-nuclear factor kappaB axis in macrophages and mice lungs. Pathobiology 86:237-247. https://doi.org/10.1159/000500628
  21. Deng M, Zhang Q, Yan L, Bian Y, Li R, Gao J, Wang Y, Miao J, Li J, Zhou X, Hou G (2023) Glycyl-L-histidyl-L-lysine-Cu2+ rescues cigarette smoking-induced skeletal muscle dysfunction via a sirtuin 1-dependent pathway. J Cachexia Sarcopenia Muscle 14:1365-1380. https://doi.org/10.1002/jcsm.13213
  22. Kennedy-Feitosa E, Okuro RT, Pinho Ribeiro V, Lanzetti M, Barroso MV, Zin WA, Porto LC, Brito-Gitirana L, Valenca SS (2016) Eucalyptol attenuates cigarette smoke-induced acute lung inflammation and oxidative stress in the mouse. Pulm Pharmacol Ther 41:11-18. https://doi.org/10.1016/j.pupt.2016.09.004
  23. van der Vaart H, Postma DS, Timens W, ten Hacken NH (2004) Acute effects of cigarette smoke on inflammation and oxidative stress: a review. Thorax 59:713-721. https://doi.org/10.1136/thx.2003.012468
  24. Ryu CS, Choi YJ, Nam HS, Jeon JS, Jung T, Park JE, Choi SJ, Lee K, Lee MY, Kim SK (2019) Short-term regulation of the hepatic activities of cytochrome P450 and glutathione S-transferase by nose-only cigarette smoke exposure in mice. Food Chem Toxicol 125:182-189. https://doi.org/10.1016/j.fct.2018.12.035
  25. Do VQ, Park KH, Seo YS, Park JM, Kim B, Kim SK, Sung JH, Lee MY (2020) Inhalation exposure to cigarette smoke induces endothelial nitric oxide synthase uncoupling and enhances vascular collagen deposition in streptozotocin-induced diabetic rats. Food Chem Toxicol 136:110988. https://doi.org/10.1016/j.fct.2019.110988
  26. Choi SJ, Lee SH, Lee SJ, Yang MJ, Lee K (2016) Subchronic inhalation toxicity study of 3R4F reference cigarette smoke in rats. Mol Cell Toxicol 12:313-325. https://doi.org/10.1007/s13273-016-0036-8
  27. Alexander DJ, Collins CJ, Coombs DW, Gilkison IS, Hardy CJ, Healey G, Karantabias G, Johnson N, Karlsson A, Kilgour JD, McDonald P (2008) Association of Inhalation Toxicologists (AIT) working party recommendation for standard delivered dose calculation and expression in non-clinical aerosol inhalation toxicology studies with pharmaceuticals. Inhal Toxicol 20:1179-1189. https://doi.org/10.1080/08958370802207318
  28. Kim JK, Kang MG, Cho HW, Han JH, Chung YH, Rim KT, Yang JS, Kim H, Lee MY (2011) Effect of nano-sized carbon black particles on lung and circulatory system by inhalation exposure in rats. Saf Health Work 2:282-289. https://doi.org/10.5491/shaw.2011.2.3.282
  29. Kim MS, Kim SH, Jeon D, Kim HY, Han JY, Kim B, Lee K (2018) Low-dose cadmium exposure exacerbates polyhexamethylene guanidine-induced lung fibrosis in mice. J Toxicol Environ Health A 81:384-396. https://doi.org/10.1080/15287394.2018.1451177
  30. Oh JM, Jung YS, Jeon BS, Yoon BI, Lee KS, Kim BH, Oh SJ, Kim SK (2012) Evaluation of hepatotoxicity and oxidative stress in rats treated with tert-butyl hydroperoxide. Food Chem Toxicol 50:1215-1221. https://doi.org/10.1016/j.fct.2012.01.031
  31. Volpi N, Tarugi P (1998) Improvement in the high-performance liquid chromatography malondialdehyde level determination in normal human plasma. J Chromatogr B Biomed Sci Appl 713:433-437. https://doi.org/10.1016/s0378-4347(98)00195-9
  32. Ryu CS, Kwak HC, Lee JY, Oh SJ, Phuong NT, Kang KW, Kim SK (2013) Elevation of cysteine consumption in tamoxifen-resistant MCF-7 cells. Biochem Pharmacol 85:197-206. https://doi.org/10.1016/j.bcp.2012.10.021
  33. Asti C, Ruggieri V, Porzio S, Chiusaroli R, Melillo G, Caselli GF (2000) Lipopolysaccharide-induced lung injury in mice. I. Concomitant evaluation of inflammatory cells and haemorrhagic lung damage. Pulm Pharmacol Ther 13:61-69. https://doi.org/10.1006/pupt.2000.0231
  34. Meyer KC (2007) Bronchoalveolar lavage as a diagnostic tool. Semin Respir Crit Care Med 28:546-560. https://doi.org/10.1055/s-2007-991527
  35. Drent M, Cobben NA, Henderson RF, Wouters EF, van Dieijen-Visser M (1996) Usefulness of lactate dehydrogenase and its isoenzymes as indicators of lung damage or inflammation. Eur Respir J 9:1736-1742. https://doi.org/10.1183/09031936.96.09081736
  36. Nishi KI, Kadoya C, Ogami A, Oyabu T, Morimoto Y, Ueno S, Myojo T (2020) Changes over time in pulmonary inflammatory response in rat lungs after intratracheal instillation of nickel oxide nanoparticles. J Occup Health 62:e12162. https://doi.org/10.1002/1348-9585.12162
  37. Song MK, Kim DI, Lee K (2020) Kathon induces fibrotic inflammation in lungs: the first animal study revealing a causal relationship between humidifier disinfectant exposure and eosinophil and Th2-mediated fibrosis induction. Molecules 25:4684. https://doi.org/10.3390/molecules25204684
  38. Banfi B, Clark RA, Steger K, Krause KH (2003) Two novel proteins activate superoxide generation by the NADPH oxidase NOX1. J Biol Chem 278:3510-3513. https://doi.org/10.1074/jbc.C200613200
  39. Cheng G, Lambeth JD (2004) NOXO1, regulation of lipid binding, localization, and activation of NOX1 by the Phox homology (PX) domain. J Biol Chem 279:4737-4742. https://doi.org/10.1074/jbc.M305968200
  40. Lyle AN, Deshpande NN, Taniyama Y, Seidel-Rogol B, Pounkova L, Du P, Papaharalambus C, Lassegue B, Griendling KK (2009) Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ Res 105:249-259. https://doi.org/10.1161/CIRCRESAHA.109.193722
  41. Kinnula VL, Ilumets H, Myllarniemi M, Sovijarvi A, Rytila P (2007) 8-Isoprostane as a marker of oxidative stress in nonsymptomatic cigarette smokers and COPD. Eur Respir J 29:51-55. https://doi.org/10.1183/09031936.00023606
  42. Kim SH, Kim JS, Shin HS, Keen CL (2003) Influence of smoking on markers of oxidative stress and serum mineral concentrations in teenage girls in Korea. Nutrition 19:240-243. https://doi.org/10.1016/s0899-9007(02)01002-x
  43. Zang LY, Stone K, Pryor WA (1995) Detection of free radicals in aqueous extracts of cigarette tar by electron spin resonance. Free Radic Biol Med 19:161-167. https://doi.org/10.1016/0891-5849(94)00236-d
  44. Orosz Z, Csiszar A, Labinskyy N, Smith K, Kaminski PM, Ferdinandy P, Wolin MS, Rivera A, Ungvari Z (2007) Cigarette smokeinduced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation. Am J Physiol Heart Circ Physiol 292:H130-H139. https://doi.org/10.1152/ajpheart.00599.2006
  45. van Rijt SH, Keller IE, John G, Kohse K, Yildirim AO, Eickelberg O, Meiners S (2012) Acute cigarette smoke exposure impairs proteasome function in the lung. Am J Physiol Lung Cell Mol Physiol 303:L814-L823. https://doi.org/10.1152/ajplung.00128.2012
  46. Braber S, Henricks PA, Nijkamp FP, Kraneveld AD, Folkerts G (2010) Inflammatory changes in the airways of mice caused by cigarette smoke exposure are only partially reversed after smoking cessation. Respir Res 11:99. https://doi.org/10.1186/1465-9921-11-99
  47. Carter CA, Misra M (2010) Effects of short-term cigarette smoke exposure on Fischer 344 rats and on selected lung proteins. Toxicol Pathol 38:402-415. https://doi.org/10.1177/0192623310364028
  48. El-Mahdy MA, Abdelghany TM, Hemann C, Ewees MG, Mahgoup EM, Eid MS, Shalaan MT, Alzarie YA, Zweier JL (2020) Chronic cigarette smoke exposure triggers a vicious cycle of leukocyte and endothelial-mediated oxidant stress that results in vascular dysfunction. Am J Physiol Heart Circ Physiol 319:H51-H65. https://doi.org/10.1152/ajpheart.00657.2019
  49. Halliwell B, Gutteridge JMC (2015) Free Radicals in Biology and Medicine. Oxford University Press, Oxford, UK. https://doi.org/10.1093/acprof:oso/9780198717478.001.0001
  50. Aranda-Rivera AK, Cruz-Gregorio A, Arancibia-Hernandez YL, Hernandez-Cruz EY, Pedraza-Chaverri J (2022) RONS and oxidative stress: an overview of basic concepts. Oxygen 2:437-478. https://doi.org/10.3390/oxygen2040030
  51. Buvelot H, Jaquet V, Krause KH (2019) Mammalian NADPH Oxidases. Methods Mol Biol 1982:17-36. https://doi.org/10.1007/978-1-4939-9424-3_2