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- Gustafsson, Åsa, et al.
(författare)
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Lung exposure of titanium dioxide nanoparticles induces innate immune activation and long-lasting lymphocyte response in the Dark Agouti rat
- 2011
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Ingår i: Journal of Immunotoxicology. - : Informa Healthcare. - 1547-691X .- 1547-6901. ; 8:2, s. 111-121
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Gustafsson, Åsa, et al.
(författare)
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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
- 2014
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Ingår i: Journal of Applied Toxicology. - : John Wiley & Sons. - 0260-437X .- 1099-1263. ; 34:3, s. 272-280
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Svensson-Elfsmark, Linda, et al.
(författare)
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Murine chitinases Ym1 and Ym2 are highly expressed in allergen-induced eosinophilic lung inflammation but not in acute neutrophilic airway response
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Mammals are incapable of producing chitin but express despite this, enzymes such as chitinases and chitinase-like proteins that are involved in the regulation of its biosynthesis. There is increasing evidence, in both human and mice, that chitinases and chitinase-like proteins are important mediators of immune responses. Studies show that two chitinase-like proteins, Ym1 and Ym2, are expressed in murine models of allergen-induced lung inflammation. The purpose of this study was to investigate whether Ym1 and Ym2 are specific markers for allergic inflammation or if they were to some extent expressed in other inflammatory settings as well. Methods: In this study, three different models for airway inflammation using C57BL/6 female mice were utilized. We induced allergic airway inflammation with a 35-day protocol using ovalbumin; chemical airway inflammation by intratracheal exposure of the alkylating nitrogen mustard analogue melphalan; and endotoxin-induced pulmonary inflammation by exposure to aerosolized lipopolysaccharide. Twenty hours after final exposure/challenge, lung tissue and cells in bronchoalveolar lavage were analyzed. Transcription of Ym1 and Ym2 mRNA was determined using real-time reverse-transcription PCR and protein expression was analyzed with 2D gel electrophoresis. Results and conclusion: We demonstrated that both Ym1 and Ym2 are specifically up-regulated in an allergic airway inflammation but not in LPS-induced or melphalan-induced airway inflammation. Based on our results we consider Ym2 a possible future candidate as a specific marker for allergic airway inflammation.
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| 4. |
- Svensson-Elfsmark, Linda, et al.
(författare)
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Rats repeatedly exposed to toluene diisocyanate exhibit immune reactivity against methyl isocyanate-protein conjugates.
- 2009
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Ingår i: International Archives of Allergy and Immunology. - : S. Karger AG. - 1018-2438 .- 1423-0097. ; 150:3, s. 229-236
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Volatile monoisocyanates are formed through thermal degradation when products containing polyurethane are heated. Repeated exposure to diisocyanates, such as toluene diisocyanate (TDI) are a well-known cause of occupational asthma. However, although monoisocyanates are abundant in occupational settings, there are few data concerning their ability to provoke immune reactions and asthma. We compared immune reactivity and respiratory disease following single or repeated inhalation exposures to the monoisocyanates methyl isocyanate (MIC) and isocyanic acid (ICA) with the effects of TDI. METHODS: Isocyanates were administrated either as single vapor exposures or as repeated intranasal instillations in rats. Adverse health effects were monitored by analyzing airway inflammation, respiratory function and weight gain. Immune reactivity caused by repeated exposures was studied by analysis of isocyanate-specific antibodies and airway infiltration of immune competent cells. RESULTS: Repeated exposures to TDI induced airway infiltration of neutrophils and lymphocytes, while neither MIC nor ICA provoked a detectable inflammatory response. Antibodies against isocyanate-albumin conjugates were detected in serum after both exposures to TDI and MIC, but not to ICA. TDI-exposed rats also displayed IgG antibodies against MIC-albumin conjugates. Even though MIC did not induce airway inflammation, single exposure provoked an increase in airway resistance and repeated exposures caused weight loss similar to that of TDI. CONCLUSIONS: Airway exposure to TDI produces an antibody response not only against TDI but also against MIC-protein conjugates. This indicates that immune reactivity against abundant monoisocyanates in occupational environments can occur in individuals pre-sensitized with low abundance but highly sensitizing diisocyanates.
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