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Inhalation of alkylating mustard causes long-term T cell-dependent inflammation in airways and growth of connective tissue
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)
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)
2011 (English)In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 280, no 3, 88-97 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2011. Vol. 280, no 3, 88-97 p.
Keyword [en]
Alkylating mustard, T lymphocytes, γδ T cells, Airway inflammation
National Category
Respiratory Medicine and Allergy
Identifiers
URN: urn:nbn:se:umu:diva-45890DOI: 10.1016/j.tox.2010.11.012PubMedID: 21129433OAI: oai:DiVA.org:umu-45890DiVA: diva2:435667
Available from: 2011-08-19 Created: 2011-08-19 Last updated: 2017-12-08Bibliographically 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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Wigenstam, ElisabethBucht, Anders

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