Skip to main content

Advertisement

SpringerLink
Log in

The Association of Cigarette Smoke Exposure with Lung Cellular Toxicity and Oxidative Stress: the Protective Role of Crocin

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Cigarette smoke (CS) contains many free radicals and toxic chemicals. Nuclear erythroid-related factor-2 (Nrf2) is a transcriptional regulator of several phase II antioxidant genes, including glutamate-cysteine ligase (GCL). In this study, it was hypothesized that Crocin may mediate antioxidant signaling pathway to protect human lung epithelial cells against CS-mediated toxicity and oxidative stress via inducing glutathione (GSH) biosynthesis and activation of Nrf2 pathway. Alveolar epithelial cells (A549) were exposed to 1, 2.5 and 5% cigarette smoke extracts (CSE) with or without Crocin (500 μM). After 48 h exposure, the cytotoxicity, oxidant/antioxidant parameters and the Nrf2 pathway modification were assayed. Treatment of A549 cells with all concentrations of CSE dose dependently decreased cell viability, antioxidant levels, GCL and Nrf2 gene expression, which was associated with increased production of reactive oxygen species. Crocin not only restored CSE-depleted GSH levels by enhancing GCL expression via activation of Nrf2 but also quenched the CSE-generation and release of reactive oxygen species. Crocin attenuated CSE-mediated Nrf2 modifications, thereby inducing its nuclear accumulation associated with GCL gene transcription leading to enhanced GSH levels. By inducing GSH synthesis, Crocin attenuates CSE-mediated GSH depletion and protects cells against CSE-induced oxidative stress via Nrf2 pathway. These results may have implications in dietary modulation of natural antioxidants in treatment of pulmonary diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Lee, J., V. Taneja, and R. Vassallo. 2012. Cigarette smoking and inflammation: Cellular and molecular mechanisms. Journal of Dental Research 91 (2): 142–149.

    Article  CAS  Google Scholar 

  2. Yaghi A, Dolovich MB.2016. Airway epithelial cell cilia and obstructive lung disease. Cells 5(4):40.

    Article  Google Scholar 

  3. Oluwole O, Arinola GO, Ana GR, Wiskel T, Huo D, Olopade OI, Olopade CO.2013. Relationship between household air pollution from biomass smoke exposure, and pulmonary dysfunction, oxidant-antioxidant imbalance and systemic inflammation in rural women and children in Nigeria. Glob J Health Sci 5(4):28.

  4. Lu SC.2009.Regulation of glutathione synthesis. Mol. Aspects Med 30; 30(1):42–59.

    Article  CAS  Google Scholar 

  5. Moskaug, J., H. Carlsen, M.C. Myhrstad, and R. Blomhoff. 2005. Polyphenols and glutathione synthesis regulation. The American Journal of Clinical Nutrition 81 (1): 277–283.

    Article  Google Scholar 

  6. Rahman I, MacNee W.1999. Lung glutathione and oxidative stress: Implications in cigarette smoke-induced airway disease. Am J Physiol Lung Cell Mol Physiol277 (18): 1067–1088.

    Article  CAS  Google Scholar 

  7. Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, Biswal S.2004. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest114: 1248–1259.

  8. Finley, J.W., and S. Gao. 2017. A perspective on Crocus sativus L. (saffron) constituent Crocin: A potent water-soluble antioxidant and potential therapy for Alzheimer’s disease. J. Agric. Food Chem 31 65 (5): 1005–1020.

    Article  CAS  Google Scholar 

  9. Singla, R.K.; Bhat, V.G.2011.Crocin: An overview. Indo Glob. J. Pharm. Sci 1(4): 281–286.

  10. Ghorbanzadeh V, Mohammadi M, Dariushnejad H, Abhari A, Chodari L, Mohaddes G.2017. Cardioprotective effect of Crocin combined with voluntary exercise in rat: Role of Mir-126 and Mir-210 in heart angiogenesis. Arquivos brasileiros de cardiologia109(1):54-62.

  11. Kamalipour M, Akhondzadeh S.2011. Cardiovascular effects of saffron: An evidence-based review. The journal of Tehran Heart Center6(2):59.

  12. Farshid AA, Tamaddonfard E, Moradi-Arzeloo M, Mirzakhani N.2016.The effects of Crocin, insulin and their co-administration on the heart function and pathology in streptozotocin-induced diabetic rats. Avicenna journal of phytomedicine6(6):658.

  13. Ghorbanzadeh, V., M. Mohammadi, G. Mohaddes, H. Dariushnejad, L. Chodari, and S. Mohammadi. 2016. Protective effect of Crocin and voluntary exercise against oxidative stress in the heart of high-fat diet-induced type 2 diabetic rats. Physiology international 103 (4): 459–468.

    Article  CAS  Google Scholar 

  14. Kim, S.H.; Lee, J.M.; Kim, S.C.; Park, C.B.; Lee, P.C.2014. Proposed cytotoxic mechanisms of the saffron carotenoids Crocin and crocetin on cancer cell lines. Biochem. Cell Biol92(2): 105–111.

    Article  CAS  Google Scholar 

  15. Kode, A., S. Rajendrasozhan, S. Caito, S.R. Yang, and I.L. Megson. 2008. Rahman I. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. American Journal of Physiology. Lung Cellular and Molecular Physiology 294 (3): 478–488.

    Article  Google Scholar 

  16. Sarshoori JR, Asadi MH, Mohammadi MT.2014. Neuroprotective effects of Crocin on the histopathological alterations following brain ischemia-reperfusion injury in rat. Iranian journal of basic medical sciences17(11):895–902.

  17. Panayiotidis MI, Stabler SP, Allen RH, Ahmad A, White CW.2004. Cigarette smoke extract increases S-adenosylmethionine and cystathionine in human lung epithelial-like (A549) cells. Chem. Biol. Interact 147(1):87–97.

    Article  CAS  Google Scholar 

  18. Wang HC, Zentner MD, Deng HT, Kim KJ, Wu R, Yang PC, Ann DK.2000. Oxidative stress disrupts glucocorticoid hormone-dependent transcription of the amiloride-sensitive epithelial sodium channel α-subunit in lung epithelial cells through ERK-dependent and thioredoxin-sensitive pathways. J. Biol. Chem24; 275(12):8600–9.

    Article  CAS  Google Scholar 

  19. Eruslanov, E., and S. Kusmartsev. 2010. Identification of ROS using oxidized DCFDA and flow-cytometry. Advanced protocols in oxidative stress II 594: 57–72.

    Article  CAS  Google Scholar 

  20. Weng X, Yan YY, Tong YH, Fan Y, Zeng JM, Wang LL, Lin NM.2016. Overexpression of Keap1 inhibits the cell proliferation and metastasis and overcomes the drug resistance in human lung cancer A549 cells. Zhonghua zhong liu za zhi [Chinese journal of oncology]38(6):404–10.

  21. Banerjee S, Chattopadhyay R, Ghosh A, Koley H, Panda K, Roy S, Chattopadhyay D, Chatterjee IB.2008. Cellular and molecular mechanisms of cigarette smoke-induced lung damage and prevention by vitamin C. Int J Inflam5(1):21.

    Article  Google Scholar 

  22. Cantin AM, Hubbard RC, Crystal RG.1989. Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis 139(2):370–2.

    Article  CAS  Google Scholar 

  23. Kim AD, Zhang R, Kang KA, You HJ, Hyun JW.2011. Increased glutathione synthesis following Nrf2 activation by vanadyl sulfate in human chang liver cells. Int. J. Mol. Sci 12(12):8878–94.

    Article  CAS  Google Scholar 

  24. Church DF, Pryor WA.1985.Free-radical chemistry of cigarette smoke and its toxicological implications. Environ Health Perspect64: 111–126.

    Article  CAS  Google Scholar 

  25. Nakayama T, Church DF, Pryor WA.1989.Quantitative analysis of the hydrogen peroxide formed in aqueous cigarette tar extracts. Free Radic Biol Med7: 9–15.

    Article  CAS  Google Scholar 

  26. Pryor WA, Stone K.1993.Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann NY Acad Sci686: 12–27.

  27. Kosmider B, Messier EM, Chu HW, Mason RJ.2011. Human alveolar epithelial cell injury induced by cigarette smoke. PLoS One 7; 6(12): e26059.

    Article  CAS  Google Scholar 

  28. Rahman, I., X.Y. Li, K. Donaldson, D.J. Harrison, and W. MacNee. 1995. Glutathione homeostasis in alveolar epithelial cells in vitro and lung in vivo under oxidative stress. American Journal of Physiology. Lung Cellular and Molecular Physiology 269: 285–292.

    Article  Google Scholar 

  29. Gebel, S., B. Gerstmayer, A. Bosio, H.J. Haussmann, E. Van Miert, and T. Muller. 2004. Gene expression profiling in respiratory tissues from rats exposed to mainstream cigarette smoke. Carcinogenesis 25: 169–178.

    Article  CAS  Google Scholar 

  30. Ahmad R, Kasim NM, Rahman T, Froemming GA, Nawawi H.2016. Antioxidant properties of saffron and Crocin and their effects on endothelial nitric oxide synthase expression in stimulated human coronary artery endothelial cells. Atherosclerosi1; 252: e158.

  31. Fiedor, J., and K. Burda. 2014. Potential role of carotenoids as antioxidants in human health and disease. Nutrients 27 6 (2): 466–488.

    Article  Google Scholar 

  32. Assimopoulou, A.N., Z. Sinakos, and V. Papageorgiou. 2005. Radical scavenging activity of Crocus sativus L. extract and its bioactive constituents. Phytother. Res 19 (11): 997–1000.

    CAS  Google Scholar 

  33. Pham TQ, Cormier F, Farnworth E, Tong VH, Van Calsteren MR.2000. Antioxidant properties of Crocin from Gardenia jasminoides Ellis and study of the reactions of Crocin with linoleic acid and Crocin with oxygen. J. Agric. Food Chem 48(5):1455–61.

    Article  CAS  Google Scholar 

  34. Kensler, T.W., N. Wakabayashi, and S. Biswal. 2007. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annual Review of Pharmacology and Toxicology 47: 89–116.

    Article  CAS  Google Scholar 

  35. Dianat M, Radan M, Badavi M, Mard SA, Bayati V, Ahmadizadeh M.2018.Crocin attenuates cigarette smoke-induced lung injury and cardiac dysfunction by anti-oxidative effects: The role of Nrf2 antioxidant system in preventing oxidative stress. Respiratory research 19(1):58-68.

  36. Chan, K., X.D. Han, and Y.W. Kan. 2001. An important function of Nrf2 in combating oxidative stress: Detoxification of acetaminophen. Proceedings of the National Academy of Sciences of the United States of America 98: 4611–4616.

    Article  CAS  Google Scholar 

  37. Chen L, Kwong M, Lu R, Ginzinger D, Lee C, Leung L, Chan JY.2003.Nrf2 is critical for redox balance and survival of liver cells duringdevelopment. Mol Cell Biol23: 4673–4686.

  38. Ischiropoulos H.2003. Biological selectivity and functional aspects of protein tyrosine nitration. Biochem Biophys Res Commun305: 776–783.

    Article  CAS  Google Scholar 

  39. Lennon CW, Cox HD, Hennelly SP, Chelmo SJ, McGuirl MA.2007. Probing structural differences in prion protein isoforms by tyrosine nitration. Biochemistry46: 4850–4860.

  40. Esterbauer H, Schaur RJ, Zollner H.1991. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med11: 81–128.

    Article  CAS  Google Scholar 

  41. Doorn JA, Petersen DR.2002.Covalent modification of amino acid nucleophiles by the lipid peroxidation products 4-hydroxy-2-nonenal and 4-oxo- 2-nonenal. Chem Res Toxicol15: 1445–1450.

  42. Marwick JA, Kirkham PA, Stevenson CS, Danahay H, Giddings J, Butler K, Donaldson K, Macnee W, Rahman I.2004.Cigarette smoke alterschromatin remodeling and induces proinflammatory genes in rat lungs. Am J Respir Cell Mol Biol31: 633–642.

  43. Moodie FM, Marwick JA, Anderson CS, Szulakowski P, Biswas SK, Bauter MR, Kilty I, Rahman I .2004.Oxidative stress and cigarette smokealter chromatin remodeling but differentially regulate NF-_B activationand proinflammatory cytokine release in alveolar epithelial cells. FASEB J18: 1897–1899.

  44. Yang SR, Chida AS, Bauter MR, Shafiq N, Seweryniak K, Maggirwar SB, Kilty I, Rahman I.2006.Cigarette smoke induces proinflammatory cytokinerelease by activation of NF-KB and posttranslational modifications ofhistone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol291: L46–L57.

  45. Dinkova-Kostova A, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M, Talalay P.2002.Direct evidence that sulfhydrylgroups of Keap1 are the sensors regulating induction of phase 2 enzymesthat protect against carcinogens and oxidants. Proc Natl Acad Sci USA99: 11908–11913.

  46. Kim, J.H., G.Y. Park, S.Y. Bang, S.Y. Park, S.K. Bae, and Y. Kim. 2014. Crocin suppresses LPS-stimulated expression of inducible nitric oxide synthase by upregulation of heme oxygenase-1 via calcium/calmodulin-dependent protein kinase 4. Mediators Inflammdoi. https://doi.org/10.1155/2014/728709.

    CAS  Google Scholar 

  47. Kim SH, Lee JM, Kim SC, Park CB, Lee PC.2014. Proposed cytotoxic mechanisms of the saffron carotenoids Crocin and crocetin on cancer cell lines. Int J Biochem CellBio92(2):105–11.

    Article  CAS  Google Scholar 

  48. El-Beshbishy HA, Hassan MH, Aly HA, Doghish AS, Alghaithy AA.2012.Crocin “saffron” protects against beryllium chloride toxicity in rats through diminution of oxidative stress and enhancing gene expression of antioxidant enzymes. Ecotoxicol. Environ. Saf1; 83: 47–54.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The source of the data used in this paper was from the Ph.D thesis (APRC-9513) of Dr. Maryam Radan, a student of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. Authors gratefully acknowledge the help and financial support of the Persian Gulf Physiology Research Center of Ahvaz Jundishapur University of Medical Sciences (APRC-9513).

Author information

Authors and Affiliations

  1. Department of Physiology, Persian Gulf Physiology Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Maryam Radan, Mahin Dianat, Mohammad Badavi & Seyyed Ali Mard

  2. Cellular and Molecular Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Vahid Bayati

  3. Persian Gulf Physiology Research Center, School of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IR, Iran

    Masoumeh Ahmadizadeh

Authors
  1. Maryam Radan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahin Dianat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammad Badavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seyyed Ali Mard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vahid Bayati
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masoumeh Ahmadizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mahin Dianat.

Ethics declarations

Conflict of Interest

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Radan, M., Dianat, M., Badavi, M. et al. The Association of Cigarette Smoke Exposure with Lung Cellular Toxicity and Oxidative Stress: the Protective Role of Crocin. Inflammation 43, 135–145 (2020). https://doi.org/10.1007/s10753-019-01102-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-019-01102-1

KEY WORDS

Search

Navigation