| 1. |
- Ekstrand-Hammarström, Barbro, et al.
(författare)
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Inhalation of alkylating mustard causes long-term T cell-dependent inflammation in airways and growth of connective tissue
- 2011
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Ingår i: Toxicology. - : Elsevier. - 0300-483X .- 1879-3185. ; 280:3, s. 88-97
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Tidskriftsartikel (refereegranskat)abstract
- Low-dose exposure of alkylating mustard gas causes long-term respiratory complications characterized by bronchitis and lung fibrosis. In this study, we utilized a mouse model for lung exposure of the nitrogen mustard melphalan, in order to define early and late events in the pathogenesis such as expression of pro-inflammatory cytokines, recruitment of inflammatory cells to airways and late-phase fibrosis. We investigated the roles of different T lymphocyte subsets on the inflammatory response by using knockout mice lacking either the genes expressing T cell receptor (TCR)αβ or TCRγδ, and compared the responsiveness with that of wild type mice and double knockout mice completely deficient in T cells. Exposure to melphalan induced an early burst of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and IL-23 in airways, followed by extensive infiltration of neutrophils in the lung tissue and airways within 24h. The acute phase was followed by a sustained lymphocytic response that persisted for at least 14 days with resulting lung fibrosis. Engagement of T lymphocytes, particularly the γδ T cell subset, was crucial both for the acute cytokine and neutrophil response and for the late-phase lung fibrosis as indicated by the lack of response in γδ T cell deficient mice. Our data demonstrate that T lymphocytes play a prominent role in the pathogenesis of long-term lung injuries caused by strong alkylating agents.
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| 2. |
- Gulin-Sarfraz, Tina, et al.
(författare)
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Feasibility Study of Mesoporous Silica Particles for Pulmonary Drug Delivery : Therapeutic Treatment with Dexamethasone in a Mouse Model of Airway Inflammation
- 2019
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 11:4
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Tidskriftsartikel (refereegranskat)abstract
- Diseases in the respiratory tract rank among the leading causes of death in the world, and thus novel and optimized treatments are needed. The lungs offer a large surface for drug absorption, and the inhalation of aerosolized drugs are a well-established therapeutic modality for local treatment of lung conditions. Nanoparticle-based drug delivery platforms are gaining importance for use through the pulmonary route. By using porous carrier matrices, higher doses of especially poorly soluble drugs can be administered locally, reducing their side effects and improving their biodistribution. In this study, the feasibility of mesoporous silica particles (MSPs) as carriers for anti-inflammatory drugs in the treatment of airway inflammation was investigated. Two different sizes of particles on the micron and nanoscale (1 mu m and 200 nm) were produced, and were loaded with dexamethasone (DEX) to a loading degree of 1:1 DEX:MSP. These particles were further surface-functionalized with a polyethylene glycol-polyethylene imine (PEG-PEI) copolymer for optimal aqueous dispersibility. The drug-loaded particles were administered as an aerosol, through inhalation to two different mice models of neutrophil-induced (by melphalan or lipopolysaccharide) airway inflammation. The mice received treatment with either DEX-loaded MSPs or, as controls, empty MSPs or DEX only; and were evaluated for treatment effects 24 h after exposure. The results show that the MEL-induced airway inflammation could be treated by the DEX-loaded MSPs to the same extent as free DEX. Interestingly, in the case of LPS-induced inflammation, even the empty MSPs significantly down-modulated the inflammatory response. This study highlights the potential of MSPs as drug carriers for the treatment of diseases in the airways.
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| 3. |
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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. |
- 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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| 6. |
- 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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| 7. |
- Wigenstam, Elisabeth, 1980-, et al.
(författare)
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Corticosteroid treatment inhibits airway hyperreactivity and lung injury in a murine model of chemical-induced airway inflammation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Context: Exposure to toxic alkylating mustard agents causes both acute and long-term effects to the lungs as indicated by increased number of inflammatory cells in airways, lung edema and lung tissue fibrosis. We have previously demonstrated that treatment with the corticosteroid dexamethasone 1 hr after lung exposure to the alkylating mustard melphalan, protect mice from acute and sub-acute inflammatory responses, as well as from lung fibrosis. Objective: In order to address the importance of early anti-inflammatory treatment, we investigated the therapeutic effect of dexamethasone administered 1, 2 or 6 hrs following exposure to melphalan. Methods: Female C57BL/6 mice were via intratracheal instillation exposed to the nitrogen mustard analogue melphalan and treated i.p. with dexamethasone 1, 2 or 6 hours after exposure. Twenty hours or 14 days post exposure mice were subjected to analysis of respiratory mechanics where the effects of incremental doses of methacholine on central and peripheral lung components were measured. We also determined the amount of neutrophils and lymphocytes in the bronchoalveolar lavage fluid and measured the amount of collagen content in the lungs. Results: Melphalan exposure exerted a significant effect on both central and peripheral respiratory function. Dexamethasone given one hour post exposure protected the lung against the damaging effects of melphalan. Collagen deposition 14 days after exposure was decreased with dexamethasone treatment. Conclusion: Early dexamethasone treatment (within one hour after exposure) is important in order to reduce the airway reactivity and inflammation caused by toxic alkylating mustards such as melphalan.
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| 8. |
- Wigenstam, Elisabeth, et al.
(författare)
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Corticosteroid treatment inhibits airway hyperresponsiveness and lung injury in a murine model of chemical-induced airway inflammation
- 2012
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 301:1-3, s. 66-71
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Tidskriftsartikel (refereegranskat)abstract
- Context: Exposure to toxic alkylating mustard agents causes both acute and long-term effects to the lungs as indicated by increased number of inflammatory cells in airways, lung edema and lung tissue fibrosis. We have previously demonstrated that treatment with the corticosteroid dexamethasone 1 h after lung exposure to the nitrogen mustard analog melphalan protects mice from acute and sub-acute inflammatory responses, as well as from lung tissue fibrosis. Objective: In order to address the importance of early anti-inflammatory treatment, we investigated the therapeutic effect of dexamethasone administered 1, 2 or 6 h following exposure to melphalan. Methods: C57BL/6 mice were exposed to melphalan and treated with dexamethasone 1,2 or 6 h after exposure. Twenty hours or 14 days post exposure mice were subjected to analysis of respiratory mechanics where the effects of incremental doses of methacholine on central and peripheral lung components were measured. We also determined the amount of inflammatory cells in the bronchoalveolar lavage fluid and measured the amount of collagen content in the lungs. Results: Melphalan exposure increased airway hyperresponsiveness in both central and peripheral airways and induced an airway inflammation dominated by infiltration of macrophages and neutrophils. Dexamethasone given 1 h after exposure to melphalan provided better protection against airway inflammation than administration 2 or 6 h after exposure. Collagen deposition 14 days after exposure was decreased due to dexamethasone treatment. Conclusion: Early treatment with dexamethasone is important in order to reduce the airway hyperresponsiveness and inflammation caused by toxic alkylating mustards such as melphalan. (c) 2012 Elsevier Ireland Ltd. All rights reserved.
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| 9. |
- 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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| 10. |
- Wigenstam, Elisabeth, et al.
(författare)
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N-acetyl cysteine improves the effects of corticosteroids in a mouse model of chlorine-induced acute lung injury
- 2015
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 328, s. 40-47
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Tidskriftsartikel (refereegranskat)abstract
- Chlorine (Cl-2) causes tissue damage and a neutrophilic inflammatory response in the airways manifested by pronounced airway hyperreactivity (AHR). The importance of early anti-inflammatory treatment has previously been addressed. In the previous study, both high-dose and low-dose of dexamethasone (DEX) decreased the risk of developing delayed effects, such as persistent lung injuries, while only high-dose treatment could significantly counteract acute-phase effects. One aim of this study was to evaluate whether a low-dose of DEX in combination with the antioxidant N-acetyl cysteine (NAC) and if different treatments (Triptolide, Reparixin and Rolipram) administered 1 h after Cl-2-exposure could improve protection against acute lung injury in Cl-2-exposed mice. BALB/c mice were exposed to 300 ppm Cl-2 during 15 min. Assessment of AHR and inflammatory cells in bronchoalveolar lavage was analyzed 24 h post exposure. Neither of DEX nor NAC reduced the AHR and displayed only minor effects on inflammatory cell influx when given as separate treatments. When given in combination, a protective effect on AHR and a significant reduction in inflammatory cells (neutrophils) was observed. Neither of triptolide, Reparixin nor Rolipram had an effect on AHR but Triptolide had major effect on the inflammatory cell influx. Treatments did not reduce the concentration of either fibrinogen or plasminogen activator inhibitor-1 in serum, thereby supporting the theory that the inflammatory response is not solely limited to the lung. These results provide a foundation for future studies aimed at identifying new concepts for treatment of chemical-induced lung injury. Studies addressing combination of anti-inflammatory and antioxidant treatment are highly motivated.
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