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Corticosteroid treatment inhibits airway hyperreactivity and lung injury in a murine model of chemical-induced airway inflammation
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)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

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.

Keyword [en]
alkylating nitrogen mustard, chemical-induced lung injury, corticosteroids, respiratory mechanics, mouse models
National Category
Medical and Health Sciences
Research subject
Lung Medicine
Identifiers
URN: urn:nbn:se:umu:diva-52717OAI: oai:DiVA.org:umu-52717DiVA: diva2:506853
Available from: 2012-03-01 Created: 2012-03-01 Last updated: 2012-03-02Bibliographically 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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