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Nanomaterials: respiratory and immunological effects following inhalation of engineered nanoparticles
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. FOI.
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 [en]
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: urn:nbn:se:umu:diva-95724ISBN: 978-91-7601-168-3 (print)OAI: oai:DiVA.org:umu-95724DiVA: diva2:762075
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
List of papers
1. Lung exposure of titanium dioxide nanoparticles induces innate immune activation and long-lasting lymphocyte response in the Dark Agouti rat
Open this publication in new window or tab >>Lung exposure of titanium dioxide nanoparticles induces innate immune activation and long-lasting lymphocyte response in the Dark Agouti rat
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
Keyword
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:nbn:se:umu:diva-45900 (URN)10.3109/1547691X.2010.546382 (DOI)000290167000002 ()21309687 (PubMedID)
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
2. Inhalation exposure of nano-scaled titanium dioxide (TiO2) particles alters the inflammatory responses in asthmatic mice
Open this publication in new window or tab >>Inhalation exposure of nano-scaled titanium dioxide (TiO2) particles alters the inflammatory responses in asthmatic mice
2013 (English)In: Inhalation Toxicology, ISSN 0895-8378, E-ISSN 1091-7691, Vol. 25, no 4, 179-191 p.Article in journal (Refereed) Published
Abstract [en]

Context: Titanium dioxide (TiO2) nanoparticles (NPs) are regarded as relatively non-toxic in concentrations occurring in occupational environments. Nevertheless, it is conceivable that adverse health effects may develop in sensitive populations such as individuals with respiratory diseases.

Objective: We investigated whether single or repeated exposure to TiO2 could aggravate inflammatory responses in naive mice and mice with ovalbumin (OVA)-induced airway inflammation.

Methods: Exposure to aerosolized TiO2 was performed during OVA sensitization, before, or during the OVA challenge period. The effects on respiratory physiology, inflammatory cells in bronchoalveolar lavage (BAL) and inflammatory mediators in BAL and serum were assessed 24 h after the last OVA challenge or TiO2 exposure.

Results: A single exposure of TiO2 had a marked effect on responses in peripheral airways and increasing infiltration of neutrophils in airways of naive animals. Marked aggravation of airway responses was also observed in animals with allergic disease provided that the single dose TiO2 was given before allergen challenge. Repeated exposures to TiO2 during sensitization diminished the OVA-induced airway eosinophilia and airway hyperresponsiveness but concomitant exposure to TiO2 during the OVA challenge period resulted in neutrophilic airway inflammation and a decline in general health condition as indicated by the loss of body weight.

Conclusion: We conclude that inhalation of TiO2 may aggravate respiratory diseases and that the adverse health effects are highly dependent on dose and timing of exposure. Our data imply that inhalation of NPs may increase the risk for individuals with allergic airway disease to develop symptoms of severe asthma.

Place, publisher, year, edition, pages
Informa Healthcare, 2013
Keyword
Asthma, inflammation, nanomaterial, respiratory mechanics, titanium dioxide
National Category
Respiratory Medicine and Allergy Pharmacology and Toxicology
Research subject
Occupational and Environmental Medicine; Immunology; Lung Medicine; nanoparticles; nanotoxicology
Identifiers
urn:nbn:se:umu:diva-71103 (URN)10.3109/08958378.2013.770939 (DOI)000317459800001 ()
Funder
FormasForte, Swedish Research Council for Health, Working Life and Welfare
Note

Forskningsfinansiär: Swedish Ministry of Defence

Available from: 2013-06-11 Created: 2013-05-20 Last updated: 2017-12-06Bibliographically approved
3. Strain differences influence timing and magnitude of both acute and late inflammatory reactions after intratracheal instillation of an alkylating agent in rats
Open this publication in new window or tab >>Strain differences influence timing and magnitude of both acute and late inflammatory reactions after intratracheal instillation of an alkylating agent in rats
2014 (English)In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 34, no 3, 272-280 p.Article in journal (Refereed) Published
Abstract [en]

The acute pulmonary responses after exposure to sulfur and nitrogen mustards are well documented whereas the late pulmonary effects are not. With a novel focus on the immune system this paper investigate whether late phase pulmonary effects developed in rats exposed to the nitrogen mustard melphalan are linked to the acute responses and whether the reactions are genetically regulated. The DA rat strain was used to establish a lung exposure model. Five other inbred rat strains (PVG, PVG.1AV1, LEW, WF and F344) were compared within the model at selected time points. All rat strains displayed a biphasic pattern of leukocyte infiltration in the lungs, dominated by neutrophils 2days after exposure and a second peak dominated by macrophages 29days after exposure. The number of macrophages was higher in the DA rat compared with the other strains. The infiltration of lymphocytes in the lungs varied in both time of appearance and magnitude between strains. The quantity of collagen deposition in the lungs varied between strains at day 90; LEW and WF displayed high collagen content which coincided with an increased level of cytotoxic T cells. LEW further displayed an increased number of T helper cells and natural killer (NK) T cells in the lungs. The results in this study suggest there is a link between the development of lung fibrosis and high cytotoxic cell responses and that there is a genetic influence, as there are variations in acute and late adverse reactions between rat strains in both timing and magnitude.

Copyright (c) 2013 John Wiley & Sons, Ltd.

Place, publisher, year, edition, pages
John Wiley & Sons, 2014
Keyword
mustard gas; melphalan; inflammation; genetic; pulmonary fibrosis
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-87155 (URN)10.1002/jat.2878 (DOI)000331174900006 ()
Available from: 2014-04-11 Created: 2014-03-24 Last updated: 2017-12-05Bibliographically approved
4. Mice with established airway inflammation exert differential cellular responses to inhaled hematite nanoparticles than healthy mice
Open this publication in new window or tab >>Mice with established airway inflammation exert differential cellular responses to inhaled hematite nanoparticles than healthy mice
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The aim of this study was to investigate the inflammatory and immunological responses in the airways and the lung-draining lymph nodes, following lung exposure to hematite nanoparticles (NPs). The responses to hematite NPs were evaluated in both non-sensitized healthy mice, and allergen-sensitized mice, in which the latter represent a group of sensitive individuals with allergic airway disease. This allergic airway disease was induced by sensitization and aerosol challenge to a respiratory allergen resulting in an established eosinophilic and lymphocytic airway inflammation at the time of NP exposure. The mice received either hematite NPs or vehicle (PBS) intratracheally and the cellular responses were evaluated on day 1, 2, and 7, following exposure.

Intratracheal instillation of hematite NPs induced an increase of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on day 1 and 2 following exposure. At these time-points the lymphocytes in the lymph nodes were also increased. In contrast, exposure to hematite NPs in sensitized mice induced a rapid and unspecific cellular reduction in the alveolar space on the first day after exposure. A similar decrease of lymphocytes was also observed in the mediastinal lymph nodes draining the airways. The study did not indicate a reduction of inflammatory cells in the lung tissue or a translocation of cells from alveolar space to lung tissue. Although, mucociliary cellular clearance could be a possible explanation, our finding of cellular decrease also in lung draining lymph nodes point at cell death as the most likely cause to this unspecific cellular reduction.

The results indicate that cells in the airways and lymph nodes of individuals with established airway inflammation undergo cell death when exposed to iron oxide NPs. A possible reason to the toxic response is extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways, which is further catalyzed by Fe ions released by the hematite NPs, or by generation of ROS at the surface of the NPs. Such cell toxic response was not detected in healthy non-sensitized individuals. This study clearly demonstrates the different response of sensitized and non-sensitized mice, and highlights the importance of including individuals with respiratory disorders, such as allergic asthma, when evaluating health effects of inhaled nanomaterials.

Keyword
Ironoxide, nanoparticles, asthma, allergy, lung, lymph node, lymphocytes, macrophages
National Category
Respiratory Medicine and Allergy Pharmacology and Toxicology
Research subject
Toxicology; Occupational and Environmental Medicine; Lung Medicine; Immunology; nanoparticles; nanotoxicology
Identifiers
urn:nbn:se:umu:diva-95969 (URN)
Funder
FormasForte, Swedish Research Council for Health, Working Life and Welfare
Note

Forskningsfinansiär: Umeå center for environmental research, Swedish Minestry of Defence

Available from: 2014-11-10 Created: 2014-11-10 Last updated: 2014-11-14Bibliographically approved

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