| 1. |
- 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. |
- Kotova, Natalia, et al.
(författare)
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Nätverk vid upptäckt av befolkningsexponering för farliga kemiska ämnen : en sammanställning av kompetens och laboratorieverksamhet bland regionala Arbets- och miljömedicinska enheter vid upptäckt av befolkningsexponering för farliga ämnen av kemiskt ursprung där livsmedel och dricksvatten kan vara en potentiell källa
- 2017
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- I Livsmedelsverkets beredskapsarbete ingår att göra uppskattningar av vilka nivåer av farliga ämnen som konsumenterna får i sig via livsmedel och att tidigt upptäcka exponering som kan resultera i skadliga hälsoeffekter. Detta arbete innebär att övervakningen behöver förbättras gällande risker för kemisk exponering. I händelse av kemisk exponering av befolkningen via livsmedel eller vatten, beroende på olyckor eller antagonistiska händelser, behövs en väl samordnad kedja inkluderande bl.a. operativa aktörer samt centrala och regionala myndigheter.Denna rapport är ett resultat av krisberedskapsprojektet Nätverk vid upptäckt av befolkningsexponering för farliga kemiska ämnen som finansierats med 2:4-anslag från MSB. Projektets syfte är att bilda ett nätverk mellan olika aktörer för att skapa förutsättningar för ett bättre utnyttjande av landets samlade kapacitet och kompetens avseende provtagnings- och laboratorieanalys i avsikt att identifiera farliga kemiska ämnen i prover från människa. Nätverket är till för att skapa en effektivare beredskap vid allvarliga händelser med kemiska ämnen och/eller för övervakning av exponering för kemiska ämnen hos den svenska befolkningen.Projektet fokuserade på att inventera och förbättra kunskapsläget och laboratorieberedskap för provtagning och analys av prover från människa vid upptäckt av befolkningsexponering för farliga ämnen. Detta gäller i livsmedel och dricksvatten då ämnen av kemiskt ursprung kan vara en potentiell farlig källa. Projektet skapade ett nätverk mellan myndigheter och regionala Arbets- och miljömedicinska (AMM) enheter för att skapa förutsättningar för ett bättre utnyttjande av landets samlade kapacitet, kompetens och laboratorier inom AMM-verksamheten. För att stärka såväl regional som nationell krisberedskap när det gäller hanteringen av oönskade händelser så har projektets alla AMM-enheter i Sverige kartlagt kompetens och laboratoriekapacitet samt testat förmågan att arbeta i fält med provtagning och efterhantering av prover.Målgruppen för rapporten är de som arbetar med identifiering och riskvärdering av farliga ämnen med kemiskt ursprung i befolkningen, både vid kris och i vardagen. Nätverkets arbete resulterade bl.a. i de manualer som används vid exponering för olika typer av CBRNE-ämnen dvs. inte enbart kemiska (C-ämnen), men också biologiska (B-ämnen), radiologiska (R-ämnen), nukleära (N-ämnen) och explosiva (E-ämnen). Projektet har drivits av Livsmedelsverket i ett nära samarbete med regionala AMM-enheter och Totalförsvarets Forskningsinstitut (FOI) samt i samverkan med Folkhälsomyndigheten, Naturvårdsverket, Socialstyrelsen, Kemikalieinspektionen och Karolinska Institutet.
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| 4. |
- 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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| 5. |
- 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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| 6. |
- Wigenstam, Elisabeth, et al.
(författare)
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Acute respiratory changes and pulmonary inflammation involving a pathway of TGF-beta 1 induction in a rat model of chlorine-induced lung injury
- 2016
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 309, s. 44-54
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Tidskriftsartikel (refereegranskat)abstract
- We investigated acute and delayed respiratory changes after inhalation exposure to chlorine (Cl-2) with the aim to understand the pathogenesis of the long-term sequelae of Cl-2-induced lung-injury. In a rat model of nose-only exposure we analyzed changes in airway hyperresponsiveness (AHR), inflammatory responses in airways, expression of pro-inflammatory markers and development of lung fibrosis during a time course from 5 h up to 90 days after a single inhalation of Cl-2. A single dose of dexamethasone (10 mg/Kg) was administered 1 h following Cl-2-exposure. A 15-min inhalation of 200 ppm Cl-2 was non-lethal in Sprague-Dawley rats. At 24 h post exposure, Cl-2-exposed rats displayed elevated numbers of leukocytes with an increase of neutrophils and eosinophils in bronchoalveolar lavage (BAL) and edema was shown both in lung tissue and the heart At 24 h, the inflammasome-associated cytokines IL-1 beta and IL-18 were detected in BAL Concomitant with the acute inflammation a significant AHR was detected. At the later time-points, a delayed inflammatory response was observed together with signs of lung fibrosis as indicated by increased pulmonary macrophages, elevated TGF-beta expression in BAL and collagen deposition around airways. Dexamethasone reduced the numbers of neutrophils in BAL at 24 h but did not influence the AHR. Inhalation of Cl-2 in rats leads to acute respiratory and cardiac changes as well as pulmonary inflammation involving induction of TGF-beta 1. The acute inflammatory response was followed by sustained macrophage response and lack of tissue repair. It was also found that pathways apart from the acute inflammatory response contribute to the Cl(2-)induced respiratory dysfunction.
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| 7. |
- Wigenstam, Elisabeth, et al.
(författare)
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Anti-inflammatory and anti-fibrotic treatment in a rodent model of acute lung injury induced by sulfur dioxide
- 2018
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Ingår i: Clinical Toxicology. - : Taylor & Francis. - 1556-3650 .- 1556-9519. ; 56:12, s. 1185-1194
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Tidskriftsartikel (refereegranskat)abstract
- Context: Inhalation of sulfur dioxide (SO2) affects the lungs and exposure to high concentrations can be lethal. The early pulmonary response after inhaled SO2 involves tissue injury, acute neutrophilic lung inflammation and airway hyperresponsiveness (AHR). In rats, long-term pulmonary fibrosis is evident 14 days post-exposure as indicated by analysis of collagen deposition in lung tissue. Early treatment with a single dose of dexamethasone (DEX,10 mg/kg) significantly attenuates the acute inflammatory response in airways. However, this single DEX-treatment is not sufficient for complete protection against SO2-induced injuries.Methods: Female Sprague–Dawley rats exposed to SO2 (2200 ppm, nose-only exposure, 10 min) were given treatments (1, 5 and 23 h after SO2-exposure) with the anti-fibrotic and anti-inflammatory substance Pirfenidone (PFD, 200 mg/kg) or DEX (10 mg/kg) to evaluate whether the inflammatory response, AHR and lung fibrosis could be counteracted.Results: Both treatment approaches significantly reduced the total leukocyte response in bronchoalveolar lavage fluid and suppressed pulmonary edema. In contrast to DEX-treatment, PFD-treatment reduced the methacholine-induced AHR to almost control levels and partially suppressed the acute mucosal damage whereas multiple DEX-treatment was the only treatment that reduced collagen formation in lung tissue.Conclusions: To enable an accurate extrapolation of animal derived data to humans, a detailed understanding of the underlying mechanisms of the injury, and potential treatment options, is needed. The findings of the present study suggest that treatments with the capability to reduce both AHR, the inflammatory response, and fibrosis are needed to achieve a comprehensive mitigation of the acute lung injury caused by SO2.
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| 8. |
- Wigenstam, Elisabeth, et al.
(författare)
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Inhaled sulfur dioxide causes pulmonary and systemic inflammation leading to fibrotic respiratory disease in a rat model of chemical-induced lung injury
- 2016
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 368, s. 28-36
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Tidskriftsartikel (refereegranskat)abstract
- Inhalation of high concentrations of sulfur dioxide (SO2) affects the lungs and can be immediately dangerous to life. We examined the development of acute and long-term effects after exposure of SO2 in Sprague-Dawley rats, in particular inflammatory responses, airway hyperresponsiveness (AHR) and lung fibrosis. Animals were subjected to a single exposure of 2200 ppm SO2 during 10 min and treated with a single dose of the anti-inflammatory corticosteroid dexamethasone 1 h following exposure. Exposed rats showed labored breathing, decreased body-weight and an acute inflammation with neutrophil and macrophage airway infiltrates 5 h post exposure. The acute effects were characterized by bronchial damage restricted to the larger bronchi with widespread injured mucosal epithelial lining. Rats displayed hyperreactive airways 24 h after exposure as indicated by increased methacholine-induced respiratory resistance. The inflammatory infiltrates remained in lung tissue for at least 14 days but at the late time-point the dominating granulocyte types had changed from neutrophils to eosinophils. Analysis of immunoregulatory and pro-inflammatory cytokines in serum and airways implicated mixed macrophage phenotypes (M-1/M-2) and T helper cell activation of both T(H)1 and T(H)2 subtypes. Increased expression of the pro-fibrotic cytokine TGF beta 1 was detected in airways 24 h post exposure and remained increased at the late time-points (14 and 28 days). The histopathology analysis confirmed a significant collagen deposition 14 days post exposure. Treatment with dexamethasone significantly counteracted the acute inflammatory response but was insufficient for complete protection against SO2-induced adverse effects, i.e. treatment only provided partial protection against AHR and the long-term fibrosis.
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