TiO2 Nanoparticles Induce Lung Fibrosis and Proteinosis through Influence on Matrix Metalloproteinase Expression

TiO2 Nanoparticles Induce Lung Fibrosis and Proteinosis through Influence on Matrix Metalloproteinase Expression

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Author(s): Fatimah A. Jasim, Dhamia K. Suker, Adnan I. AL- Badran

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DOI: 10.18483/ijSci.1197 237 663 1-13 Volume 6 - Mar 2017


Background: nanotechnology applications, speared very quickly while very little has been done to measure and assess the hazard of nanoparticles (NPs) to an ecosystem and to the biological systems. Lung exposure to titanium dioxide nanoparticle (TiO2 NP) may induce pulmonary alveolar proteinases and fibrosis through influence on matrix metalloproteinase expression (MMPs). Methods: In order to study this, TiO2 NP was instilled into the lung, then, histopathological alteration and MMPs (MMP-1, MMP-2, Collagen-I) expression using RT-qPCR were assessed at 4 days, a month and 3 months post-instillation. Data were analyzed using ANOVA test and gene expression was normalized to that of housekeeping gene, which was hypoxanthine phosphoribosyltransferase (HPRT). Results: The results showed that TiO2 NP induces acute inflammation in lung tissue after 4 days post-instillation with significantly decrease (p<0.05) in MMPs expression. While inducing fibrosis and proteinosis with significantly increase (p<0.05) in MMPs expression after a month post- instillation. Otherwise, after 3 months post-instillation the fibrosis and proteinosis were decreased and the expression significantly increased (p<0.05). Conclusion: TiO2 NP induces many alterations in lung structure after 4 days and a month from intratracheal instillation this included metaplasia in bronchus epithelial and in alveolar epithelial, Fibrosis, angiogenesis and proteinaceous through affected on MMPs expression which decreased the expression of MMP-1, MMP-2, MMP-12 and Collagen-I in the lung.


Lung fibrosis, Pulmonary alveolar proteinosis, TiO2 NPs, MMPs


  1. Garg, A., Visht, S., Sharma, P. K. & Kumar, N. Formulation, Characterization and Application on Nanoparticle: A Review. Der Pharmacia Sinica, 2011; 2(2), 17–26.
  2. Ambalavanan, N., Stanishevsky, A., Bulger, A., Halloran, B., Steele, C., Vohra, Y., & Matalon, S. Titanium oxide nanoparticle instillation induces inflammation and inhibits lung development in mice. American Journal of Physiology. Lung Cellular and Molecular Physiology, 2013; 304(3), L152-61.
  3. Powell, J. J., Harvey, R. S., Ashwood, P., Wolstencroft, R., Gershwin, M. E., & Thompson, R. P. H. Immune potentiation of ultrafine dietary particles in normal subjects and patients with inflammatory bowel disease. Journal of Autoimmunity, 2000; 14(1), 99–105.
  4. Jackson, B. C., Nebert, D. W., & Vasiliou, V. Update of human and mouse matrix metalloproteinase families. Human Genomics, 2010; 4(3), 194–201.
  5. Giannandrea, M., & Parks, W. CDiverse functions of matrix metalloproteinases during fibrosis. Disease Models & Mechanisms, 2014; 7(2), 193–203.
  6. Burnham, E. L., Janssen, W. J., Riches, D. W. H., Moss, M., & Downey, G. P. The fibroproliferative response in acute respiratory distress syndrome: mechanisms and clinical significance. Eur. Respir. J., 2014; 43(1), 276–285.
  7. Fu Y., Zhang Y., Chang X., Zhang Y., Ma S., Sui J., Yin L., Pu Y.& Liang G. Systemic Immune Effects of Titanium Dioxide Nanoparticles after Repeated Intratracheal Instillation in Rat. Int. J. Mol. Sci., 2014; 15, 6961-6973.
  8. Abd Al-abbas, M. J. MLST of S Aureus Isolates Identified by 16SrRNA Gene Sequencing. Lambert Academic Publishing. 2012; 221pp.
  9. Liu R., Yin L., Pu Y., Liang G., Zhang J., Su Y., Xiao Z. & Ye B. Pulmonary toxicity induced by three forms of titanium dioxide nanoparticles via intratracheal instillation in rats. Progress in Natural Science, 2009; 19, 573–579.
  10. Shinohara, N., Oshima, Y., Kobayashi, T., Imatanaka, N., Nakai, M., Ichinose, T., … Gamo, M. Dose-dependent clearance kinetics of intratracheally administered titanium dioxide nanoparticles in rat lung. Toxicology, 2014; 325.
  11. Abu-Dief, E. E., Khalil, K. M., Abdel-Aziz, H. O., Nor-Eldin, E. & Ragab, E. E. Histological Effects of Titanium Dioxide Nanoparticles in Adult Male Albino Rat Liver and Possible Prophylactic Effects of Milk Thistle Seeds. Life Science Journal, 2015;12(2), 115–123.
  12. Baisch, B. L., Corson, N. M., Wade-Mercer, P., Gelein, R., Kennell, A. J., Oberdörster, G., & Elder, A. Equivalent titanium dioxide nanoparticle deposition by intratracheal instillation and whole body inhalation: the effect of dose rate on acute respiratory tract inflammation. Particle and Fibre Toxicology, 2014.;11, 5.
  13. Drury, R. A. B., Wallington, E. A. & Carmeron, Sir R. Carleton’s histological technique. 4th ed. Oxford university Press, London, England. 1967, pp:129-133,166-176.
  14. Roulet A., Armand L., Dagouassat M., Rogerieux F., Simon-Deckers A., Belade E., Nhieu J. T. V., Lanone S., Pairon J.-C., Lacroix G. & Boczkowski J. Intratracheally administered titanium dioxide or carbon black nanoparticles do not aggravate elastase-induced pulmonary emphysema in rats. BMC Pulmonary Medicine, 2012; 12:38.
  15. Sakata, Y., Yamamoto, K., Mano, T., Nishikawa, N., Yoshida, J., Hori, M., Miwa, T., and Masuyama, T. Activation of matrix metalloproteinases precedes left ventricular remodeling in hypertensive heart failure rats: Its inhibition as a primary effect of angiotensin-converting enzyme inhibitor. Circulation. 2004; 109:2143-2149.
  16. Ma, L., Zhao, J., Wang, J., Liu, J., Duan, Y., Liu, H., … Hong, F. The Acute Liver Injury in Mice Caused by Nano-Anatase TiO2. Nanoscale Research Letters, 2009; 4, 1275–1285.
  17. Li, J., Li, Q., Xu, J., Li, J., Cai, X., Liu, R., … Li, W. Comparative study on the acute pulmonary toxicity induced by 3 and 20 nm TiO2 primary particles in mice. Environmental Toxicology and Pharmacology, 2007; 24(3), 239–244.
  18. Amara, S., Khemissi, W., Mrad, I., Rihane, N., Slama, I. B., Mir, M. E., … Sakly, M. Effect of TiO2 nanoparticles on emotional behavior and biochemical parameters in adult Wistar rats. General Physiology and Biophysics, 2013; 32, 229–234.
  19. Bermudez, E., Mangum, J. B., Asgharian, B., Wong, B. A., Reverdy, E. E., Janszen, D. B., … Everitt, J. I. Long-term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium dioxide particles. Toxicological Sciences, 2002; 70(1), 86–97.
  20. Duan, Y., Liu, J., Ma, L., Li, N., Liu, H., Wang, J., … Hong, F. Toxicological characteristics of nanoparticulate anatase titanium dioxide in mice. Biomaterials, 2010; 31(5), 894–899.
  21. Hussain, S., Boland, S., Baeza-Squiban, A., Hamel, R., Thomassen, L. C. J., Martens, J. A., … Marano, F.. Oxidative stress and proinflammatory effects of carbon black and titanium dioxide nanoparticles: Role of particle surface area and internalized amount. Toxicology, 2009; 260(1–3), 142–149.
  22. Kendall, R. T., & Feghali-Bostwick, C. A. Fibroblasts in fibrosis: Novel roles and mediators. Frontiers in Pharmacology, 2014; 5 MAY(May), 1–13.
  23. Cho, W. S., Duffin, R., Thielbeer, F., Bradley, M., Megson, I. L., MacNee, W., … Donaldson, K. Zeta potential and solubility to toxic ions as mechanisms of lung inflammation caused by metal/metal oxide nanoparticles. Toxicological Sciences, 2012; 126(2), 469–477.
  24. Porter, D. W., Wu, N., Hubbs, A. F., Mercer, R. R., Funk, K., Meng, F., … Holian, A. Differential mouse pulmonary dose and time course responses to titanium dioxide nanospheres and nanobelts. Toxicological Sciences, 2013; 131(1), 179–193.
  25. Silva, R. M., Teesy, C., Franzi, L., Weir, A., Westerhoff, P., Evans, J. E., & Pinkerton, K. E. Biological response to nano-scale titanium dioxide (TiO2): role of particle dose, shape, and retention. Journal of Toxicology and Environmental Health. Part A, 2013; 76(16), 953–972.
  26. Scarino, A., Noël, A., Renzi, P. M., Cloutier, Y., Vincent, R., Truchon, G., … & Charbonneau, M. Impact of emerging pollutants on pulmonary inflammation in asthmatic rats: ethanol vapors and agglomerated TiO2 nanoparticles. Inhalation Toxicology, 2012; 24(8), 528–538.
  27. Bermudez, E., Mangum, J. B., Asgharian, B., Wong, B. A., Reverdy, E. E., Janszen, D. B., … Everitt, J. I. Long-term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium dioxide particles. Toxicological Sciences, 2002; 70(1), 86–97.
  28. Davis, J., Wang, a, & Shtakin, J. Nanomaterial Case Studies: Nanoscale Titanium Dioxide in Water Treatment and in Topical Sunscreen. US EPA: Research Triangle Park, NC, (November) 2010.
  29. Ostiguy, C., Soucy, B., Lapointe, G., Woods, C., Menard, L., & Trottier, M. Health Effects of Nanoparticles. Chemical Substances and Biological Agents. Studies and Research Projects. (second ed.), 2008; Montréal.
  30. Esa, S. A., Rawy, A. M., El-behissy, M. M., & Kamel, M. H. Study of the level of sputum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor metalloproteinase-1 (TIMP-1) in COPD patients. Egyptian Journal of Chest Diseases and Tuberculosis, 2016; 65, 303–309.
  31. Pardo, A., Sandra, C., Maldonado, M., & Moisés, S. Role of matrix metalloproteinases in the pathogenesis of idiopathic pulmonary fibrosis. Respiratory Research, 2016; 17(23), 1–10.
  32. Safranek, J., Pesta, M., Holubec, L., Kulda, V., Dreslerova, J., Vrzalova, J., … Treska, V. Expression of MMP-7, MMP-9, TIMP-1 and TIMP-2 mRNA in lung tissue of patients with non-small cell lung cancer (NSCLC) and benign pulmonary disease. Anticancer Research, 2009; 29(7), 2513–2517.
  33. Armand, L., Dagouassat, M., Belade, E., Simon-Deckers, A., Le Gouvello, S., Tharabat, C., … Lanone, S. Titanium dioxide nanoparticles induce matrix metalloprotease 1 in human pulmonary fibroblasts partly via an interleukin-1b-Dependent mechanism. American Journal of Respiratory Cell and Molecular Biology, 2013; 48(3), 354–363.
  34. Robert, S., Gicquel, T., Victoni, T., Valença, S., Barreto, E., Bailly-Maître, B., … Lagente, V. Involvement of matrix metalloproteinases (MMPs) and inflammasome pathway in molecular mechanisms of fibrosis. Bioscience Reports, 2016; 36(4), 1–11.
  35. Gaggar, A, Hector, A, Bratcher, P. E., Mall, M. a, Griese, M., & Hartl, D. The role of matrix metalloproteinases in cystic fibrosis lung disease. The European Respiratory Journal, 2011; 38(3), 721–7.
  36. Geraghty, P., Rogan, M. P., Greene, C. M., Boxio, R. M. M., Poiriert, T., O’Mahony, M., … McElvaney, N. G. Neutrophil Elastase Up-Regulates Cathepsin B, and Matrix Metalloprotease-2 Expression. The Journal of Immunology, 2007; 178(9), 5871–5878.
  37. Greenlee, K. J., Werb, Z., & Kheradmand, F. Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted. Physiological Reviews, 2007; 87(1), 69–98.

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International Journal of Sciences is Open Access Journal.
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