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Murine chitinases Ym1 and Ym2 are highly expressed in allergen-induced eosinophilic lung inflammation but not in acute neutrophilic airway response
Division of CBRN Defence and Security, Swedish Defence Research Agency, Umeå, Sweden.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. (Division of CBRN Defence and Security, Swedish Defence Research Agency, Umeå, Sweden)
Swedish University of Agricultural Sciences, Department of Molecular Biosciences, the Biomedical Centre, Uppsala, Sweden.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. (Division of CBRN Defence and Security, Swedish Defence Research Agency, Umeå, Sweden)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Mammals are incapable of producing chitin but express despite this, enzymes such as chitinases and chitinase-like proteins that are involved in the regulation of its biosynthesis. There is increasing evidence, in both human and mice, that chitinases and chitinase-like proteins are important mediators of immune responses. Studies show that two chitinase-like proteins, Ym1 and Ym2, are expressed in murine models of allergen-induced lung inflammation. The purpose of this study was to investigate whether Ym1 and Ym2 are specific markers for allergic inflammation or if they were to some extent expressed in other inflammatory settings as well.

Methods: In this study, three different models for airway inflammation using C57BL/6 female mice were utilized. We induced allergic airway inflammation with a 35-day protocol using ovalbumin; chemical airway inflammation by intratracheal exposure of the alkylating nitrogen mustard analogue melphalan; and endotoxin-induced pulmonary inflammation by exposure to aerosolized lipopolysaccharide. Twenty hours after final exposure/challenge, lung tissue and cells in bronchoalveolar lavage were analyzed. Transcription of Ym1 and Ym2 mRNA was determined using real-time reverse-transcription PCR and protein expression was analyzed with 2D gel electrophoresis.

Results and conclusion: We demonstrated that both Ym1 and Ym2 are specifically up-regulated in an allergic airway inflammation but not in LPS-induced or melphalan-induced airway inflammation. Based on our results we consider Ym2 a possible future candidate as a specific marker for allergic airway inflammation.

Keyword [en]
chitinases, chitinase-like proteins, Ym1, Ym2, inflammation
National Category
Medical and Health Sciences
Research subject
Lung Medicine
Identifiers
URN: urn:nbn:se:umu:diva-52716OAI: oai:DiVA.org:umu-52716DiVA: diva2:506849
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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