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Lung exposure of titanium dioxide nanoparticles induces innate immune activation and long-lasting lymphocyte response in the Dark Agouti rat
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
2011 (English)In: Journal of Immunotoxicology, ISSN 1547-691X, E-ISSN 1547-6901, Vol. 8, no 2, 111-121 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Informa Healthcare, 2011. Vol. 8, no 2, 111-121 p.
Keyword [en]
Nanoparticles, TiO2, lung, inflammation, NK cells, T-cells, dendritic cells
National Category
Pharmacology and Toxicology Respiratory Medicine and Allergy
Research subject
Occupational and Environmental Medicine; Lung Medicine; nanoparticles; Immunology; nanotoxicology
Identifiers
URN: urn:nbn:se:umu:diva-45900DOI: 10.3109/1547691X.2010.546382ISI: 000290167000002PubMedID: 21309687OAI: oai:DiVA.org:umu-45900DiVA: diva2:435693
Funder
FormasForte, Swedish Research Council for Health, Working Life and Welfare
Note

Forskningsfinansiär: Swedish Ministry of Defence

Available from: 2011-08-19 Created: 2011-08-19 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Nanomaterials: respiratory and immunological effects following inhalation of engineered nanoparticles
Open this publication in new window or tab >>Nanomaterials: respiratory and immunological effects following inhalation of engineered nanoparticles
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Nanotechnology is an important and promising field that can lead to improved environment and human health and contribute to a better social and economic development. Materials in nanoscale have unique physiochemical properties which allow for completely new technical applications. Enlarged surface area and properties due to quantum physics are among the properties that distinguish the nanoscale. Nano safety has evolved as a discipline to evaluate the adverse health effects from engineered nanomaterials (ENMs). The prevalence of allergic diseases is increasing in the society. An additional issue is the influence of inherited factors on the health responses to ENMs. The aim of this thesis was to investigate the respiratory, inflammatory, and immunological effects following inhalation of ENMs; both sensitive and genetically susceptible individuals were used. Sensitive individuals refer to individuals with pre-existing respiratory diseases, such as allergic asthma, and genetically susceptible individuals refer to individuals prone to autoimmune and allergic diseases.

Methods In vivo models of mice and rats were used. In study I the inflammatory and immune responses following exposure to titanium dioxide nanoparticles (TiO2 NPs) were investigated. The effect of when the TiO2 NP exposure occurs during the development of allergic airway inflammation was investigated in study II, with regards to respiratory, inflammatory, and immune responses. In study III, the influence of the genetics on the respiratory, inflammatory, and immune responses, following TiO2 NP exposure to naïve and sensitive rats was evaluated. In study IV, the inflammatory and immune responses of naïve mice and mice with an allergic airway inflammation were studied in lung fluid and lymph nodes draining the airways following inhalation to hematite NPs (α-Fe2O2).

Results Exposure to TiO2 NPs induced a long-lasting lymphocytic response in the airways, indicating a persistent immune stimulation. The dose and timing of TiO2 NP exposure affected the airway response in mice with allergic airway disease. When the mice were exposed to particles and an allergen during the same period, a decline in general health was observed. By comparing different inbred rat strains it was demonstrated that genetically determined factors influence the immune and respiratory responses to TiO2 NP exposure in both naïve and sensitive individuals. Exposure to hematite NPs resulted in different cellular responses: naïve mice had increased numbers of cells while mice with allergic airway inflammation had decreased cell numbers in BALF. Analogous cell responses were also observed in the lung draining lymph nodes.

Conclusion Altogether, this thesis emphasises the complexity of assessing health risks associated with nanoparticle exposure and the importance of including sensitive populations when evaluating adverse health effects of ENMs.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2014. 78 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1686
Keyword
nanoparticles, nanomaterials, inhalation, lung, metalloxides
National Category
Respiratory Medicine and Allergy
Research subject
Immunology; Toxicology; Lung Medicine; Occupational and Environmental Medicine; nanoparticles; nanotoxicology
Identifiers
urn:nbn:se:umu:diva-95724 (URN)978-91-7601-168-3 (ISBN)
Public defence
2014-12-05, Hörsal 135, Allmänmedicin, byggnad 9B, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Funder
FormasForte, Swedish Research Council for Health, Working Life and Welfare
Note

Forskningsfinansiär: Umeå Center for Environmental Research, and by the Swedish Ministry of Defence

Available from: 2014-11-14 Created: 2014-11-04 Last updated: 2014-11-14Bibliographically approved

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Gustafsson, ÅsaBucht, Anders

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