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Treatment with dexamethasone or liposome-encapsuled vitamin E provides beneficial effects after chemical-induced lung injury.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. (Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden)
Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. (Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden)
2009 (English)In: Inhalation Toxicology, ISSN 0895-8378, E-ISSN 1091-7691, Vol. 21, no 11, 958-964 p.Article in journal (Refereed) Published
Abstract [en]

The pathogenesis of lung injury by exposure to highly toxic sulfur and nitrogen mustards involves alkylating damage of the respiratory epithelium followed by an acute inflammatory response and lung edema. The acute phase is followed by long-term respiratory complications characterized by bronchitis, lung fibrosis, and airway hyperreactivity. In this study, we utilized a mouse model for airway inflammation induced by inhalation exposure to the alkylating nitrogen mustard melphalan, in order to investigate possible beneficial treatment effects by the corticosteroid dexamethasone. In addition, we investigated therapeutic efficacy of liposome-encapsuled vitamin E, an antioxidant formulation previously shown to be efficient in counteracting inflammatory conditions. Influx of inflammatory cells to airways, edema formation, and expression of different cytokines were analyzed 6 and 18 hours after exposure to melphalan. In order to evaluate long-term lung effects, we also investigated collagen deposition and accumulation of lymphocytes at 2 and 4 weeks after exposure. A single intraperitoneal injection of dexamethasone (10 mg/kg body weight) 1 hour after melphalan exposure significantly reduced interleukin (IL)-1 and IL-6 in bronchoalveolar lavage fluid (BALF) and diminished the acute airway inflammation. Our results also indicate that early single-dose treatment with dexamethasone protects against long-term effects observed 2-4 weeks after melphalan exposure, as indicated by reduced lymphocytic response in airways and decreased collagen deposition. Furthermore, our results indicate that also vitamin E (50 mg/kg) reduces acute inflammatory cell influx, and suppresses collagen formation in lung tissue, indicating that this drug could be used in combination with corticosteroids for protection against chemical-induced lung injury.

Place, publisher, year, edition, pages
2009. Vol. 21, no 11, 958-964 p.
National Category
Respiratory Medicine and Allergy
Identifiers
URN: urn:nbn:se:umu:diva-31032DOI: 10.1080/08958370802596298PubMedID: 19572781OAI: oai:DiVA.org:umu-31032DiVA: diva2:290558
Available from: 2010-01-27 Created: 2010-01-27 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Pathogenesis and treatment of chemical-induced lung injury
Open this publication in new window or tab >>Pathogenesis and treatment of chemical-induced lung injury
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Inhalation of chemical substances can cause irritation to airways and in high doses acute airway injury. When mice are exposed to the alkylating nitrogen mustard analogue melphalan they develop an acute airway inflammation with a rapid influx of neutrophils to the lungs. The acute phase is followed by long-term respiratory complications characterized by bronchitis, lung fibrosis, and airway hyperreactivity.     

In this thesis, a mouse model for chemical airway inflammation was established and the effects on the lungs in a time span from 6 hours up to 3 months were investigated in order to study both acute effects and possible chronic injury. We find that treatment with corticosteroids, e.g. dexamethasone, effectively blocks the inflammatory reaction in several ways: Neutrophil influx to the lungs is diminished, the expression of the proinflammatory cytokines interleukin (IL) -6 and IL-1b is decreased and edema formation as well as development of lung fibrosis is mitigated. In acute airway inflammation we show that the antioxidant vitamin E can be used as a possible complement to corticosteroids but not as a replacement since it causes insufficient downregulation of the inflammatory response. We show the importance of the T lymphocytes as they play a prominent role in the pathogenesis of long-term lung injuries caused by melphalan. Especially the minor gd T cell subset is of major importance orchestrating a number of responses including the acute cytokine and neutrophil response and late-phase lung fibrosis.

In order to find the critical time for dexamethasone treatment, mice were exposed to melphalan, treated with dexamethasone at specific time points and lung physiology and airway reactivity was measured in anaesthetized, tracheostomized mice using a small animal ventilator. From these results we conclude that an early treatment, i.e. within one hour after exposure, with dexamethasone is needed to prevent chronic lung injury. 

This thesis was undertaken with the main goal to better understand the pathogenesis of melphalan-induced airway inflammation. We believe that our findings have shed new light in this area of research and hope that this increased knowledge may be of future clinical use.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2012. 65 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1468
Keyword
chemical-induced lung injury, dexamethasone, melphalan, vitamin E, respiratory mechanics
National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
Identifiers
urn:nbn:se:umu:diva-52738 (URN)978-91-7459-337-2 (ISBN)
Public defence
2012-03-30, Norrlands Universitetssjukhus 6A-L, Biomedicinhuset, Sal E04, byggnad 6E, Umeå universitet, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-03-09 Created: 2012-03-01 Last updated: 2012-03-02Bibliographically approved

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