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Concomitant administration of nitric oxide and glucocorticoids improves protection against bronchoconstriction in a murine model of asthma
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
2010 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 109, no 2, 521-531 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2010. Vol. 109, no 2, 521-531 p.
Keyword [en]
airway inflammation, glucocorticoid sensitivity, nitric oxide, lung mechanics, murine models
National Category
Medical and Health Sciences
Research subject
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-107060DOI: 10.1152/japplphysiol.01317.2009ISI: 000280758800034PubMedID: 20538845OAI: oai:DiVA.org:uu-107060DiVA: diva2:227609
Available from: 2009-07-15 Created: 2009-07-15 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Lung mechanics and airway inflammation in murine models of asthma
Open this publication in new window or tab >>Lung mechanics and airway inflammation in murine models of asthma
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Lungmekanik och luftvägsinflammation i djurmodeller för astma
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 468
Keyword
allergic asthma, airway inflammation, murine models, lung mechanics, forced oscillation technique, airway reactivity, deep inhalations, oxidative stress, nitric oxide, glucocorticoids.
National Category
Physiology
Research subject
Clinical Physiology
Identifiers
urn:nbn:se:uu:diva-107061 (URN)978-91-554-7569-7 (ISBN)
Public defence
2009-09-11, Enghoffsalen, Akademiska Sjukhuset, Ingång 50, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2009-08-21 Created: 2009-07-15 Last updated: 2009-08-21Bibliographically approved

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