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Radiation-induced changes in breathing frequency and lung histology of C57BL/6J mice are time- and dose-dependent

Strahleninduzierte Veränderungen der Atemfrequenz und Lungenhistologie bei C57BL/6J-Mäusen sind zeit- und dosisabhängig

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Abstract

Purpose

Pneumonitis and fibrosis constitute serious adverse effects of radiotherapy in the thoracic region. In this study, time-course and dose-dependence of clinically relevant parameters of radiation-induced lung injury in C57BL/6J mice were analyzed. A well-characterized disease model is necessary for the analysis of the cellular and molecular mechanisms using genetically modified mice.

Material and methods

C57BL/6J mice received single dose right hemithorax irradiation with 12.5 or 22.5 Gy. Body weight and breathing frequency were recorded as parameters for health impairment. Lung tissue was collected over 24 weeks for histological analysis.

Results

Hemithorax irradiation with 12.5 or 22.5 Gy induced biphasic breathing impairment with the first increase between days 7 and 70. Although breathing impairment was more pronounced in the 22.5 Gy group, it was accompanied in both dose groups by pneumonitis-associated histological changes. A second rise in breathing frequency ratios became visible starting on day 70 with a steady increase until day 210. Again, breathing was more strongly affected in the 22.5 Gy group. However, breathing impairment coincided only in the 22.5 Gy group with a significant increase in collagen deposition in the lung tissue by day 210. Tissue inflammation and fibrosis were observed in the irradiated and the shielded lungs, pointing toward involvement of systemic effects.

Conclusion

Hemithorax irradiation induces time-dependent pneumonitis and fibrosis in C57BL/6J mice. While hemithorax irradiation with 12.5 Gy is sufficient to induce lung inflammation, it is below the threshold for collagen deposition and fibrosis development by day 210.

Zusammenfassung

Ziel

Pneumonitis und Lungenfibrose sind dosislimitierende Nebenwirkungen einer Strahlentherapie im Bereich des Thorax. In der vorliegenden Studie wurden Zeit- und Dosisabhängigkeit klinisch relevanter Parameter strahleninduzierter Nebenwirkungen der Lunge bei C57BL/6J-Mäusen untersucht. Ein gut definiertes Krankheitsmodell ist Voraussetzung für die Aufklärung molekularer und zellulärer Mechanismen strahleninduzierter Spätfolgen mithilfe genetisch veränderter Mäuse.

Material und Methoden

Der rechte Hemithorax von C57BL/6J-Mäusen wurde mit einer Einzeldosis 12,5 oder 22,5 Gy bestrahlt. Als klinisch relevante Toxizitätsparameter wurden Körpergewicht und Atemfrequenz analysiert. Für histologische Analysen wurde Lungengewebe über 24 Wochen zu definierten Zeitpunkten entnommen.

Ergebnisse

Die Hemithorax-Bestrahlung mit 12,5 oder 22,5 Gy induzierte einen biphasischen Anstieg der Atemfrequenzen, wobei der Anstieg in der 22,5-Gy-Gruppe jeweils stärker ausgeprägt war, als in der 12,5-Gy-Gruppe. Im Rahmen der 1. Phase zwischen Tag 7 und 70 war der Atemfrequenzanstieg bei beiden Dosisgruppen mit Pneumonitis-typischen histologischen Veränderungen assoziiert. Ein zweiter, kontinuierlicher Anstieg der Atemfrequenzen wurde zwischen Tag 70 und Tag 210 beobachtet. Allerdings wurde nur in der 22,5-Gy-Gruppe ein signifikanter Anstieg der für die Lungenfibrose charakteristischen Kollagendeposition nachgewiesen. Strahleninduzierte Pneumonitis und Fibrose traten sowohl in der bestrahlten als auch in der abgeschirmten Lunge auf, was auf eine Beteiligung systemischer Effekte hindeutet.

Schlussfolgerung

Eine Bestrahlung des Hemithorax induziert zeit- und dosisabhängig Pneumonitis und Fibrose bei C57BL/6J-Mäusen. Die Einzeit-Radiotherapie (RT) mit 12,5 Gy reicht aus, um entzündliche Veränderungen des Lungengewebes hervorzurufen, wogegen eine gesteigerte Kollagendeposition, ein Charakteristikum der Fibrose, die Applikation höherer Strahlendosen erfordert.

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Acknowledgements

We acknowledge M. Wehrman (Institute of Pathology, University Hospital Tuebingen, Germany), K. Nowak, R. Boras (Department of Radiation Oncology, University of Tuebingen), and A. Cwejn (Department of Animal Physiology, University of Tuebingen) for excellent technical support. We thank E. Kienzle (Department of Orthopedic Surgery, University Hospital Tuebingen, Germany) and J. Hennenlotter (Department of Urology, University Hospital Tuebingen, Germany) for providing technical equipment. This work was funded by grants to V.J. and C.B. from the Deutsche Krebshilfe/Mildred-Scheel-Stiftung (107388) and to T.E. by the Doctoral Programme“Cellular mechanisms of immune-associated processes” GK 794, University of Tuebingen, Germany.

Conflict of interest

The corresponding author states that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Radiation Oncology, University Hospital of Tuebingen, Tuebingen, Germany

    T. Eldh, F. Heinzelmann, A. Velalakan, C. Belka & V. Jendrossek

  2. Department of Radiation Oncology, Heinrich Heine University, Duesseldorf, Duesseldorf, Germany

    W. Budach

  3. Department of Radiation Oncology, University of Munich, Munich, Germany

    C. Belka

  4. Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Virchowstr. 173, 45122, Essen, Germany

    V. Jendrossek

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  1. T. Eldh
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Correspondence to V. Jendrossek.

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Eldh, T., Heinzelmann, F., Velalakan, A. et al. Radiation-induced changes in breathing frequency and lung histology of C57BL/6J mice are time- and dose-dependent. Strahlenther Onkol 188, 274–281 (2012). https://doi.org/10.1007/s00066-011-0046-3

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