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Strain differences influence timing and magnitude of both acute and late inflammatory reactions after intratracheal instillation of an alkylating agent in rats
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.
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. Vol. 34, no 3, 272-280 p.
Keyword [en]
mustard gas; melphalan; inflammation; genetic; pulmonary fibrosis
National Category
Pharmacology and Toxicology
URN: urn:nbn:se:umu:diva-87155DOI: 10.1002/jat.2878ISI: 000331174900006OAI: diva2:711682
Available from: 2014-04-11 Created: 2014-03-24 Last updated: 2014-11-13Bibliographically 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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