| 1. |
- Bergquist, Maria, et al.
(författare)
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Comprehensive multiplexed protein quantitation delineates eosinophilic and neutrophilic experimental asthma
- 2014
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Ingår i: BMC Pulmonary Medicine. - : Springer Science and Business Media LLC. - 1471-2466. ; 14, s. 110-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Improvements in asthma diagnosis and management require deeper understanding of the heterogeneity of the complex airway inflammation. We hypothesise that differences in the two major inflammatory phenotypes of asthma; eosinophilic and neutrophilic asthma, will be reflected in the lung protein expression profile of murine asthma models and can be delineated using proteomics of bronchoalveolar lavage (BAL). Methods: BAL from mice challenged with ovalbumin (OVA/OVA) alone (standard model of asthma, here considered eosinophilic) or OVA in combination with endotoxin (OVA/LPS, model of neutrophilic asthma) was analysed using liquid chromatography coupled to high resolution mass spectrometry, and compared with steroid-treated animals and healthy controls. In addition, conventional inflammatory markers were analysed using multiplexed ELISA (Bio-Plex T assay). Multivariate statistics was performed on integrative proteomic fingerprints using principal component analysis. Proteomic data were complemented with lung mechanics and BAL cell counts. Results: Several of the analysed proteins displayed significant differences between the controls and either or both of the two models reflecting eosinophilic and neutrophilic asthma. Most of the proteins found with mass spectrometry analysis displayed a considerable increase in neutrophilic asthma compared with the other groups. Conversely, the larger number of the inflammatory markers analysed with Bio-Plex T analysis were found to be increased in the eosinophilic model. In addition, major inflammation markers were correlated to peripheral airway closure, while commonly used asthma biomarkers only reflect central inflammation. Conclusion: Our data suggest that the commercial markers we are currently relying on to diagnose asthma subtypes are not giving us comprehensive or specific enough information. The analysed protein profiles allowed to discriminate the two models and may add useful information for characterization of different asthma phenotypes.
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| 2. |
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| 3. |
- Hjoberg, Josephine
(författare)
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The hyperosmolar airway : Mechanisms of reduced response to nitric oxide
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inhaled nitric oxide (NO) relaxes smooth muscle of the airways and of pulmonary blood vessels and is used to treat lung diseases where the pulmonary vessels are constricted. NO has also been tested as a bronchodilator in asthmatic patients. Inhaled NO is a powerful therapeutic agent, but about one-third of the patients do not respond to the treatment.It was hypothesised that variations in thedegree of airway wall oedema could account for the variable responses to inhaled NO. After creation of airway wall oedema in mechanically ventilated rabbits, by inhalation of nebulised hypertonic saline, inhaled NO could no longer dilate methacholine-constricted airways. An increase in the ionconcentration, the osmolarity, on the airway surface produced by hyperventilating the rabbits with dry air also blocked the relaxation induced by NO. The mechanism underlying this lack of response to NO in a hyperosmolar airway was further investigated with guinea pig tracheal perfusion methods in vitro.When the osmolarity was increased on the mucosal side of guinea pig trachea in vitro, the relaxation induced by the NO donor sodium nitroprusside (SNP) was diminished. Hyperosmolarity dehydrated the mucosa and submucosa, but blocking of the epithelial dehydration with amiloride did not affect the response to SNP. The decrease in response to NO in the hyperosmolar airway was not due to dysfunction of the tracheal smooth muscle and the most likely-explanation is that the NO molecule becomes bound or inactivated and does not reach the airway smooth muscle. Removal of NO scavenging superoxide anions with superoxide dismutase (SOD) increased the relaxing effect of SNP. In conclusion, increased osmolarity on the airway epithelium leads to reducedairway relaxation by NO. The suggested mechanism of this reduction is the generation of superoxide anions that inactivate the NO molecule.
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| 4. |
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| 5. |
- Jonasson, Sofia, et al.
(författare)
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Allergen-induced formation of F2-isoprostanes in a murine asthma model identifies oxidative stress in acute airway inflammation in vivo
- 2009
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Ingår i: Prostaglandins, Leukotrienes and Essential Fatty Acids. - : Elsevier BV. - 0952-3278 .- 1532-2823. ; 80:1, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- F2-isoprostanes have been associated with various forms of oxidant stress. The levels of F2-isoprostanes in a murine asthma model were studied both in situ and in vivo and further investigated whether the formation of F2-isoprostanes was associated with increased ovalbumin (OVA)-induced airway inflammation after a 17-day (OVA-17) or a 24-day (OVA-24) protocol. Bronchial reactivity was assessed by using a ventilator (FlexiVent). OVA-treated animals had higher lung resistance and lung compliance compared to control groups (P<0.001). 8-Iso-PGF2α levels in bronchoalveolar lavage (BAL) and 8-iso-PGF2α immunoreactivity in lung tissue were analyzed. OVA-17 mice showed a 2.5-fold increased level of 8-iso-PGF2α in BAL compared to PBS-17 mice (P=0.023). Lung tissue from OVA-24 mice had more intense 8-iso-PGF2α staining compared to OVA-17 mice. This study showed an accumulation of F2-isoprostanes in acute airway inflammation and a markedly increased tissue damage caused by oxidative stress in an ongoing inflammation.
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| 6. |
- Jonasson, Sofia, 1980-, et al.
(författare)
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Comparisons of effects of intravenous and inhaled methacholine on airway physiology in a murine asthma model
- 2009
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Ingår i: Respiratory Physiology & Neurobiology. - : Elsevier BV. - 1569-9048 .- 1878-1519. ; 165:2-3, s. 229-236
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Tidskriftsartikel (refereegranskat)abstract
- Airway responses to intravenous (i.v.) and inhaled (i.h.) delivery of methacholine (MCh) in BALB/c and C57BL/6 mouse strains have been compared with and without ovalbumin (OVA)-induced airway inflammation. Bronchial reactivity to MCh was assessed in anaesthetised and tracheostomised animals by using an animal ventilator (flexiVent). We partitioned the response of the lungs into airway and parenchymal components in order to compare the contributions of the airways with those of the lung parenchyma to the pulmonary mechanical responses resulting from different routes of MCh administration. Our results indicate disparate physiological responses. Intravenous MCh delivery induced a higher maximum lung resistance than i.h. MCh in OVA-treated BALB/c mice but not in C57BL/6 mice. Inhaled MCh delivery led to a significantly larger fall in lung compliance and a greater impact on peripheral airways than i.v. MCh in both strains. In conclusion, i.v. and i.h. MCh produced disparate effects in different murine strains and variant responses in inflamed airways and healthy controls. The two methods of MCh delivery have important advantages but also certain limitations with regard to measuring airway reactivity in a murine model of allergic asthma.
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| 7. |
- Jonasson, Sofia, 1980-, et al.
(författare)
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Concomitant administration of nitric oxide and glucocorticoids improves protection against bronchoconstriction in a murine model of asthma
- 2010
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 109:2, s. 521-531
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids (GC) remain the first choice of treatment in asthma, but GC therapy is not always effective and is associated with side effects. In a porcine study in our laboratory, simultaneous administration of GC and nitric oxide (NO) attenuated the endotoxin-induced inflammatory response and made GC treatment more effective than inhaled NO or steroids alone. In the present study, we aimed to further investigate the interactions between NO and GC treatment in two murine models of asthma. Inflammation was induced by endotoxin, ovalbumin, or a combination of both. With an animal ventilator and a forced oscillation method (FlexiVent), lung mechanics and airway reactivity to methacholine in response to various treatments were assessed. We also describe histology and glucocorticoid receptor (GR) protein expression in response to inhaled NO treatment [40 ppm NO gas or NO donors sodium nitroprusside (SNP) or diethylamine NONOate (DEA/NO)]. SNP and GC provided protection against bronchoconstriction to a similar degree in the model of severe asthma. When GC-treated mice were given SNP, maximum airway reactivity was further reduced. Similar effects were seen after DEA/NO delivery to GC-treated animals. Using 1-H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one (ODQ), a soluble guanylate cyclase inhibitor, we found this effect of NO donors to be mediated through a cGMP-independent mechanism. In the severe model, prolonged NO treatment restored or even increased the nuclear levels of GR. In conclusion, in our murine model of severe asthma GC treatment provided protection to only a limited degree against bronchoconstriction, while concomitant treatment with a NO donor was markedly more potent than the use of either NO or GC alone.
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| 8. |
- Jonasson, Sofia, et al.
(författare)
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Different effects of deep inspirations on central and peripheral airways in healthy and allergen-challenged mice
- 2008
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 9:23
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Deep inspirations (DI) have bronchodilatory and bronchoprotective effects in healthy human subjects, but these effects appear to be absent in asthmatic lungs. We have characterized the effects of DI on lung mechanics during mechanical ventilation in healthy mice and in a murine model of acute and chronic airway inflammation. METHODS: Balb/c mice were sensitized to ovalbumin (OVA) and challenged with nebulized OVA for 1 week or 12 weeks. Control mice were challenged with PBS. Mice were randomly selected to receive DI, which was given twice during the minute before assessment of lung mechanics. RESULTS: DI protected against bronchoconstriction of central airways in healthy mice and in mice with acute airway inflammation, but not when OVA-induced chronic inflammation was present. DI reduced lung resistance induced by methacholine from 3.8+/-0.3 to 2.8+/-0.1 cmH2O*s*mL-1 in healthy mice and 5.1+/-0.3 to 3.5+/-0.3 cmH2O*s*mL-1 in acute airway inflammation (both P < 0.001). In healthy mice, DI reduced the maximum decrease in lung compliance from 15.9+/-1.5% to 5.6+/-0.6% (P < 0.0001). This protective effect was even more pronounced in mice with chronic inflammation where DI attenuated maximum decrease in compliance from 44.1+/-6.6% to 14.3+/-1.3% (P < 0.001). DI largely prevented increased peripheral tissue damping (G) and tissue elastance (H) in both healthy (G and H both P < 0.0001) and chronic allergen-treated animals (G and H both P < 0.0001). CONCLUSIONS: We have tested a mouse model of potential value for defining mechanisms and sites of action of DI in healthy and asthmatic human subjects. Our current results point to potent protective effects of DI on peripheral parts of chronically inflamed murine lungs and that presence of DI may blunt airway hyperreactivity.
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| 9. |
- Jonasson, Sofia, 1980-
(författare)
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Lung mechanics and airway inflammation in murine models of asthma
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Allergic asthma is an inflammatory disease of the airways and is characterized by eosinophilic inflammation and increased airway reactivity. In the studies presented in this thesis, lung mechanics and measurements of airway reactivity were assessed in anaesthetized tracheostomized mice by using an animal ventilator (flexiVent®). A forced oscillation technique makes it possible to measure of both airway and tissue mechanics with a potential to distinguish between central and peripheral airways. The results of the experiments on lung mechanics imply that it is important to understand how altered lung mechanics can affect the airway physiology in order to assess the relevance of different animal models of asthma. We have investigated the effects of changing different components of the lung mechanical measurements, such as administering bronchoconstrictive agents via inhalation or intravenously and implementing deep inhalation in animals with airway inflammation. We have also investigated the relation between airway inflammation and oxidative stress. We found that the formation and time-course of F2-isoprostanes, a marker of oxidative stress, and tissue damage were associated with the degree of inflammation and with the degree of heterogeneous airway airflow. Finally we wished to investigate the hypothesis that nitric oxide (NO) may interact with glucocorticoid (GC) treatment because we see a potential for finding new strategies to increase the therapeutic effect in poor responders or patients resistant to GC treatment. NO plays a central role in physiological regulation of the airway function, and is involved in asthma. We found that the concomitant administration of NO and GC attenuated the airway reactivity more than either treatment alone. In conclusion, with the information presented in this thesis, we hope to contribute to the development of better experimental tools and to improved understanding of murine models of asthma for investigating and understanding the underlying pathophysiology of asthma.
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| 10. |
- Krenn, Claus G., et al.
(författare)
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Maintaining nitric oxide-induced airway relaxation with superoxide dismutase
- 2007
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Ingår i: Nitric oxide. - : Elsevier BV. - 1089-8603 .- 1089-8611. ; 16:4, s. 419-424
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Tidskriftsartikel (refereegranskat)abstract
- Background We have previously shown that the protective effect of inhaled nitric oxide (iNO) against methacholine-induced bronchoconstriction is negated in airways subjected to hyperosmotic stress. In this study, hypothesizing that the impaired efficiency of iNO was caused by release of reactive oxygen radicals, we examined the effect of the radical scavenging enzyme superoxide dismutase (SOD). Methods Hemodynamic and respiratory measurements were performed on anesthetized rabbits after (1) inhalation of methacholine (MCh), (2) iNO (80 ppm), followed by MCh, (3) inhalation of hypertonic saline (HS), followed by iNO and MCh and (4) pre-treatment with inhalation of SOD, followed by HS, iNO and MCh. We analyzed plasma for a marker of oxidative stress, 8-iso-prostaglandin (PG)F2α and for a marker of activation of COX-mediated inflammatory cascades, PGF2α metabolite. Results Pre-treatment with SOD restored the bronchoprotective response to iNO in hyperosmotic airways. No direct effect was seen by SOD treatment on levels of 8-iso-PGF2α, but this marker of oxidative stress correlated positively with increased bronchoconstriction. Hyperosmotic challenge elevated levels of PGF2α metabolite, and pre-treatment with SOD protected against this activation of the inflammatory cascade. Conclusion SOD pre-treatment restores the relaxant effects of iNO in hyperosmotically challenged airways by attenuating oxidative stress and activation of COX-mediated inflammatory cascades.
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| 11. |
- Swedin, Linda, et al.
(författare)
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Dissociation of airway inflammation and hyperresponsiveness by cyxloogynease inhibition in allergen challenged mice
- 2009
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 34:1, s. 200-208
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the current study was to define how cyclooxygenase (COX)-activity affects airway hyperresponsiveness (AHR) and inflammation using interventions with COX inhibitors at different time points during allergen challenge and/or prior to measurement of AHR in an eosinophil-driven allergic mouse model. Inflammatory cells were assessed in bronchioalveolar lavage (BAL) and AHR was evaluated as the total lung resistance to methacholine (MCh) challenge. Administration of FR122047 (COX-1 inhibitor) during ovalbumin (OVA) challenge and prior to MCh challenge enhanced AHR without affecting the inflammatory cell response. In contrast, administration of lumiracoxib (COX-2 inhibitor) during the same time period had no effect on AHR but reduced the inflammatory cells in BAL. Nonselective COX inhibition with diclofenac both enhanced the AHR and reduced the inflammatory cells. Administration of diclofenac only during OVA challenge reduced the cells in BAL without any changes in AHR, whereas administration of diclofenac only prior to MCh challenge enhanced AHR but did not affect the cells in BAL. The present study implicates distinct roles of prostanoids generated along the COX-1 and COX-2 pathways and, furthermore, that inflammatory cells in BAL do not change in parallel with AHR. These findings support the fact that AHR and the inflammatory response are distinct and, at least in part, uncoupled events.
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| 12. |
- Waern, Ida, et al.
(författare)
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Mouse mast cell protease 4 is the major chymase in murine airways and has a protective role in allergic airway inflammation
- 2009
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 183:10, s. 6369-6376
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Tidskriftsartikel (refereegranskat)abstract
- It is widely established that mast cells (MCs) have a harmful role in asthma, for example by secreting various proinflammatory substances stored within their secretory granule. However, in this study, we show that one of the substances stored within MC granule, chymase, in fact has a protective role in allergic airway inflammation, indicating that MCs may possess both harmful and protective activities in connection with this type of disease. Wild-type (WT) mice and mice lacking mouse MC protease 4 (mMCP-4), a chymase that is functionally homologous to human chymase, were sensitized and challenged with OVA, followed by the assessment of airway physiology and inflammatory parameters. Our results show that the airway hyperresponsiveness was significantly higher in mMCP-4(-/-) as compared with WT mice. Moreover, the degree of lung tissue inflammation was markedly higher in mice lacking mMCP-4 than in WT controls. Histological analysis revealed that OVA sensitization/challenge resulted in a marked increased in the thickness of the smooth muscle cell (SMC) layer and, notably, that the degree of SMC layer thickening was more pronounced in mMCP-4(-/-) animals than in WT controls, thus indicating that chymase may have an effect on airway SMCs. In support of this, mMCP-4-positive MCs were located in the close vicinity of the SMC layer, mainly in the upper airways, and mMCP-4 was shown to be the major chymase expressed in these MCs. Taken together, our results indicate that chymase present in the upper airways protects against allergic airway responses, possibly by regulating SMCs.
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