Brief Article
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World J Gastroenterol. Sep 14, 2012; 18(34): 4729-4735
Published online Sep 14, 2012. doi: 10.3748/wjg.v18.i34.4729
Titanium dioxide induced inflammation in the small intestine
Carolina Maciel Nogueira, Walter Mendes de Azevedo, Maria Lucia Zaidan Dagli, Sérgio Hiroshi Toma, André Zonetti de Arruda Leite, Maria Laura Lordello, Iêda Nishitokukado, Carmen Lúcia Ortiz-Agostinho, Maria Irma Seixas Duarte, Marcelo Alves Ferreira, Aytan Miranda Sipahi
Carolina Maciel Nogueira, André Zonetti de Arruda Leite, Maria Laura Lordello, Iêda Nishitokukado, Carmen Lúcia Ortiz-Agostinho, Aytan Miranda Sipahi, Department of Gastroenterology, Laboratory of Clinical and Experimental Gastroenterology, School of Medicine, University of São Paulo, Cerqueira César, 01246-900 São Paulo, Brazil
Walter Mendes de Azevedo, Department of Fundamental Chemistry, Federal University of Pernambuco, Cidade Universitária, 50670-901 Recife, Brazil
Maria Lucia Zaidan Dagli, Department of Pathology, Veterinary Medicine School, University of São Paulo, Cidade Universitária, 05508-270 São Paulo, Brazil
Sérgio Hiroshi Toma, Laboratory of Supramolecular Chemistry and Nanotechnology, Chemistry Institute, University of São Paulo, Cidade Universitária, 05513-970 São Paulo, Brazil
Maria Irma Seixas Duarte, Laboratory of Transmissible Disease, Medicine School, University of São Paulo, Cerqueira César, 01246-900 São Paulo, Brazil
Marcelo Alves Ferreira, Laboratory of Cellular Biology, Medicine School, University of São Paulo, Cerqueira César, 01246-900 São Paulo, Brazil
Author contributions: Nogueira CM is the main researcher to perform the present study; de Azevedo WM synthetized TiO2 nanoparticles; Dagli MLZ carried out histopathological evaluation of tissue; Toma SH helped and supported in all matters related to micro- and nanoparticles providing information on how to store and handle them as well as on how to prevent particle aggregation before their use in animals, and also determined the size and phase of particles; Duarte MIS helped standardize immunohistochemistry reactions; Leite AZA helped standardize the experimental protocol and most of the experiments; Lordello ML, Nishitokukado I, Ortiz-Agostinho CL helped in most of the experiments; Ferreira MA provided the transmission eletron mycroscopy images of the particles; and Sipahi AM designed the study.
Supported by The Fundação de Amparo à Pesquisa do Estado de São Paulo
Correspondence to: Dr. Aytan Miranda Sipahi, Department of Gastroenterology, Laboratory of Clinical and Experimental Gastroenterology (LIM 07), School of Medicine, University of São Paulo, Av. Dr. Arnaldo 455, Cerqueira César, 01246-900 São Paulo, Brazil. aytan@usp.br
Telephone: +55-11-30617279 Fax: +55-11-30617279
Received: September 28, 2011
Revised: May 31, 2012
Accepted: June 15, 2012
Published online: September 14, 2012
Abstract

AIM: To investigate the effects of titanium dioxide (TiO2) nanoparticles (NPTiO2) and microparticles (MPTiO2) on the inflammatory response in the small intestine of mice.

METHODS: Bl 57/6 male mice received distilled water suspensions containing TiO2 (100 mg/kg body weight) as NPTiO2 (66 nm), or MPTiO2 (260 nm) by gavage for 10 d, once a day; the control group received only distilled water. At the end of the treatment the duodenum, jejunum and ileum were extracted for assessment of cytokines, inflammatory cells and titanium content. The cytokines interleukin (IL)-1b, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-23, tumor necrosis factor-α (TNF-α), intracellular interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) were evaluated by enzyme-linked immunosorbent assay in segments of jejunum and ileum (mucosa and underlying muscular tissue). CD4+ and CD8+ T cells, natural killer cells, and dendritic cells were evaluated in duodenum, jejunum and ileum samples fixed in 10% formalin by immunohistochemistry. The titanium content was determined by inductively coupled plasma atomic emission spectrometry.

RESULTS: We found increased levels of T CD4+ cells (cells/mm2) in duodenum: NP 1240 ± 139.4, MP 1070 ± 154.7 vs 458 ± 50.39 (P < 0.01); jejunum: NP 908.4 ± 130.3, MP 813.8 ± 103.8 vs 526.6 ± 61.43 (P < 0.05); and ileum: NP 818.60 ± 123.0, MP 640.1 ± 32.75 vs 466.9 ± 22.4 (P < 0.05). In comparison to the control group, the groups receiving TiO2 showed a statistically significant increase in the levels of the inflammatory cytokines IL-12, IL-4, IL-23, TNF-α, IFN-γ and TGF-β. The cytokine production was more pronounced in the ileum (mean ± SE): IL-12: NP 33.98 ± 11.76, MP 74.11 ± 25.65 vs 19.06 ± 3.92 (P < 0.05); IL-4: NP 17.36 ± 9.96, MP 22.94 ± 7.47 vs 2.19 ± 0.65 (P < 0.05); IL-23: NP 157.20 ± 75.80, MP 134.50 ± 38.31 vs 22.34 ± 5.81 (P < 0.05); TNFα: NP 3.71 ± 1.33, MP 5.44 ± 1.67 vs 0.99 ± 019 (P < 0.05); IFNγ: NP 15.85 ± 9.99, MP 34.08 ± 11.44 vs 2.81 ± 0.69 (P < 0.05); and TGF-α: NP 780.70 ± 318.50, MP 1409.00 ± 502.20 vs 205.50 ± 63.93 (P < 0.05).

CONCLUSION: Our findings indicate that TiO2 particles induce a Th1-mediated inflammatory response in the small bowel in mice.

Keywords: Titanium dioxide; Microparticles; Nanoparticles; Immune response; Small intestine; Mice