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Mice with established airway inflammation exert differential cellular responses to inhaled hematite nanoparticles than healthy mice
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. FOI.
Ångström Laboratory, Uppsala University.
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(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 [en]
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
URN: urn:nbn:se:umu:diva-95969OAI: diva2:762067
FormasForte, Swedish Research Council for Health, Working Life and Welfare

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
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.
Umeå University medical dissertations, ISSN 0346-6612 ; 1686
nanoparticles, nanomaterials, inhalation, lung, metalloxides
National Category
Respiratory Medicine and Allergy
Research subject
Immunology; Toxicology; Lung Medicine; Occupational and Environmental Medicine; nanoparticles; nanotoxicology
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)
FormasForte, Swedish Research Council for Health, Working Life and Welfare

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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