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Lung exposure of titanium dioxide nanoparticles induces innate immune activation and long-lasting lymphocyte response in the Dark Agouti rat.

Gustafsson Å, Lindstedt E, Elfsmark LS, Bucht A - J Immunotoxicol (2011)

Bottom Line: Inhalation of metal oxide nanoparticles in high doses may lead to both acute and long-standing adverse effects.Lymphocytes recruited to the lungs were predominantly CD4(+) helper T-cells, but we also demonstrated presence of CD8(+) T-cells, B-cells, and CD25(+) T-cells.In serum, we detected both an early cytokine expression at Days 1-2 (IL-2, IL-4, IL-6, CINC-1, IL-10, and interferon-gamma [IFN-γ] and a second response at Day 16 of tumor necrosis factor-alpha (TNF-α), indicating systemic late-phase effects in addition to the local response in airways.

View Article: PubMed Central - PubMed

Affiliation: Division of CBRN Defense and Security, Swedish Defense Research Agency, Umeå, Sweden. asa.gustafsson@foi.se

ABSTRACT
Nanomaterial of titanium dioxide (TiO(2)) is manufactured in large-scale production plants, resulting in risks for accidental high exposures of humans. Inhalation of metal oxide nanoparticles in high doses may lead to both acute and long-standing adverse effects. By using the Dark Agouti (DA) rat, a strain disposed to develop chronic inflammation following exposure to immunoactivating adjuvants, we investigated local and systemic inflammatory responses after lung exposure of nanosized TiO(2) particles up to 90 days after intratracheal instillation. TiO(2) induced a transient response of proinflammatory and T-cell-activating cytokines (interleukin [IL]-1α, IL-1β, IL-6, cytokine-induced neutrophil chemoattractant [CINC]-1, granulocyte-macrophage colony-stimulating factor [GM-CSF], and IL-2) in airways 1-2 days after exposure, accompanied by an influx of eosinophils and neutrophils. Neutrophil numbers remained elevated for 30 days, whereas the eosinophils declined to baseline levels at Day 8, simultaneously with an increase of dendritic cells and natural killer (NK) cells. The innate immune activation was followed by a lymphocyte expansion that persisted throughout the 90-day study. Lymphocytes recruited to the lungs were predominantly CD4(+) helper T-cells, but we also demonstrated presence of CD8(+) T-cells, B-cells, and CD25(+) T-cells. In serum, we detected both an early cytokine expression at Days 1-2 (IL-2, IL-4, IL-6, CINC-1, IL-10, and interferon-gamma [IFN-γ] and a second response at Day 16 of tumor necrosis factor-alpha (TNF-α), indicating systemic late-phase effects in addition to the local response in airways. In summary, these data demonstrate a dynamic response to TiO(2) nanoparticles in the lungs of DA rats, beginning with an innate immune activation of eosinophils, neutrophils, dendritic cells, and NK cells, followed by a long-lasting activation of lymphocytes involved in adaptive immunity. The results have implications for the assessment of risks for adverse and persistent immune stimulation following nanoparticle exposures in sensitive populations.

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Lung sections from rat tissue showing particle uptake at Days 2 (A and B), 30 (C and D), and 90 (E and F) post-nano-TiO2 exposure. Particle aggregates (arrows) can be found in alveolar macrophages at Days 2 and 30, and mainly in the interstitium at Day 90. The tissues were stained with hematoxylin-eosin. (See colour version of this figure online at http://www.informahealthcare.com/imt)
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fig7: Lung sections from rat tissue showing particle uptake at Days 2 (A and B), 30 (C and D), and 90 (E and F) post-nano-TiO2 exposure. Particle aggregates (arrows) can be found in alveolar macrophages at Days 2 and 30, and mainly in the interstitium at Day 90. The tissues were stained with hematoxylin-eosin. (See colour version of this figure online at http://www.informahealthcare.com/imt)

Mentions: Morphological examination of lung tissue sections 2 days after exposure revealed free particle aggregates in close association to terminal bronchioles and alveolar ducts. A minor uptake of particle aggregates in alveolar macrophages (AM) was observed (Figure 7). Thirty days post-exposure, the presence of particle aggregates in macrophages had increased and few free particle aggregates were seen. At Day 90, particle aggregates were predominantly found within the macrophages. The macrophages were doubled in size and contained larger amounts of vacuoles, compared with the macrophages at Day 30. We also observed cell-shaped areas of aggregates, possibly as a consequence of disrupted cells due to particle “overload” (Oberdörster et al., 1992). To evaluate possible fibrosis, tissue sections were stained for collagen deposition at Day 90 post-exposure, but histo-pathological examination revealed no lung tissue fibrosis, epithelial injury, or granuloma formation in TiO2-exposed animals (data not shown).


Lung exposure of titanium dioxide nanoparticles induces innate immune activation and long-lasting lymphocyte response in the Dark Agouti rat.

Gustafsson Å, Lindstedt E, Elfsmark LS, Bucht A - J Immunotoxicol (2011)

Lung sections from rat tissue showing particle uptake at Days 2 (A and B), 30 (C and D), and 90 (E and F) post-nano-TiO2 exposure. Particle aggregates (arrows) can be found in alveolar macrophages at Days 2 and 30, and mainly in the interstitium at Day 90. The tissues were stained with hematoxylin-eosin. (See colour version of this figure online at http://www.informahealthcare.com/imt)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3104284&req=5

fig7: Lung sections from rat tissue showing particle uptake at Days 2 (A and B), 30 (C and D), and 90 (E and F) post-nano-TiO2 exposure. Particle aggregates (arrows) can be found in alveolar macrophages at Days 2 and 30, and mainly in the interstitium at Day 90. The tissues were stained with hematoxylin-eosin. (See colour version of this figure online at http://www.informahealthcare.com/imt)
Mentions: Morphological examination of lung tissue sections 2 days after exposure revealed free particle aggregates in close association to terminal bronchioles and alveolar ducts. A minor uptake of particle aggregates in alveolar macrophages (AM) was observed (Figure 7). Thirty days post-exposure, the presence of particle aggregates in macrophages had increased and few free particle aggregates were seen. At Day 90, particle aggregates were predominantly found within the macrophages. The macrophages were doubled in size and contained larger amounts of vacuoles, compared with the macrophages at Day 30. We also observed cell-shaped areas of aggregates, possibly as a consequence of disrupted cells due to particle “overload” (Oberdörster et al., 1992). To evaluate possible fibrosis, tissue sections were stained for collagen deposition at Day 90 post-exposure, but histo-pathological examination revealed no lung tissue fibrosis, epithelial injury, or granuloma formation in TiO2-exposed animals (data not shown).

Bottom Line: Inhalation of metal oxide nanoparticles in high doses may lead to both acute and long-standing adverse effects.Lymphocytes recruited to the lungs were predominantly CD4(+) helper T-cells, but we also demonstrated presence of CD8(+) T-cells, B-cells, and CD25(+) T-cells.In serum, we detected both an early cytokine expression at Days 1-2 (IL-2, IL-4, IL-6, CINC-1, IL-10, and interferon-gamma [IFN-γ] and a second response at Day 16 of tumor necrosis factor-alpha (TNF-α), indicating systemic late-phase effects in addition to the local response in airways.

View Article: PubMed Central - PubMed

Affiliation: Division of CBRN Defense and Security, Swedish Defense Research Agency, Umeå, Sweden. asa.gustafsson@foi.se

ABSTRACT
Nanomaterial of titanium dioxide (TiO(2)) is manufactured in large-scale production plants, resulting in risks for accidental high exposures of humans. Inhalation of metal oxide nanoparticles in high doses may lead to both acute and long-standing adverse effects. By using the Dark Agouti (DA) rat, a strain disposed to develop chronic inflammation following exposure to immunoactivating adjuvants, we investigated local and systemic inflammatory responses after lung exposure of nanosized TiO(2) particles up to 90 days after intratracheal instillation. TiO(2) induced a transient response of proinflammatory and T-cell-activating cytokines (interleukin [IL]-1α, IL-1β, IL-6, cytokine-induced neutrophil chemoattractant [CINC]-1, granulocyte-macrophage colony-stimulating factor [GM-CSF], and IL-2) in airways 1-2 days after exposure, accompanied by an influx of eosinophils and neutrophils. Neutrophil numbers remained elevated for 30 days, whereas the eosinophils declined to baseline levels at Day 8, simultaneously with an increase of dendritic cells and natural killer (NK) cells. The innate immune activation was followed by a lymphocyte expansion that persisted throughout the 90-day study. Lymphocytes recruited to the lungs were predominantly CD4(+) helper T-cells, but we also demonstrated presence of CD8(+) T-cells, B-cells, and CD25(+) T-cells. In serum, we detected both an early cytokine expression at Days 1-2 (IL-2, IL-4, IL-6, CINC-1, IL-10, and interferon-gamma [IFN-γ] and a second response at Day 16 of tumor necrosis factor-alpha (TNF-α), indicating systemic late-phase effects in addition to the local response in airways. In summary, these data demonstrate a dynamic response to TiO(2) nanoparticles in the lungs of DA rats, beginning with an innate immune activation of eosinophils, neutrophils, dendritic cells, and NK cells, followed by a long-lasting activation of lymphocytes involved in adaptive immunity. The results have implications for the assessment of risks for adverse and persistent immune stimulation following nanoparticle exposures in sensitive populations.

Show MeSH
Related in: MedlinePlus