Low-dose lung radiotherapy for COVID-19 lung disease: a preclinical efficacy study in a bleomycin model of pneumonitis

Jackson, M. R. et al. (2021) Low-dose lung radiotherapy for COVID-19 lung disease: a preclinical efficacy study in a bleomycin model of pneumonitis. International Journal of Radiation Oncology, Biology, Physics, (doi: 10.1016/j.ijrobp.2021.08.029) (PMID:34478832) (PMCID:PMC8406661) (In Press)

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Abstract

Purpose: Low-dose whole lung radiotherapy (LDLR) has been proposed as a treatment for patients with acute respiratory distress syndrome associated with SARS-CoV-2 infection and clinical trials are underway. There is an urgent need for preclinical evidence to justify this approach and inform dose, scheduling and mechanisms of action. Materials and methods: Female C57BL/6 mice were treated with intranasal bleomycin sulphate (7.5 or 11.25 units/kg, day 0), then exposed to whole lung radiation therapy (0.5, 1.0, 1.5 Gy or sham, day 3). Bodyweight was measured daily and lung tissue harvested for histology and flow cytometry on day 10. Computed tomography (CT) lung imaging was performed pre-radiation (day 3) and pre-endpoint (day 10). Results: Bleomycin caused pneumonitis of variable severity which correlated with weight loss. LDLR at 1.0 Gy was associated with a significant increase in the proportion of mice recovering to 98% of initial bodyweight and a proportion of these mice exhibited less severe histopathological lung changes. Mice experiencing moderate initial weight loss were more likely to respond to LDLR than those experiencing severe initial weight loss. Additionally, LDLR (1.0 Gy) significantly reduced bleomycin-induced increases in interstitial macrophages, CD103+ dendritic cells and neutrophil-DC hybrids. Overall, bleomycin-treated mice exhibited significantly higher percentages of non-aerated lung in left than right lungs and LDLR (1.0 Gy) limited further reductions in aerated lung volume in right but not left lungs. LDLR at 0.5 and 1.5 Gy did not improve bodyweight, flow cytometric or radiological readouts of bleomycin-induced pneumonitis. Conclusions: Our data support the concept that LDLR can ameliorate acute inflammatory lung injury, identify 1.0 Gy as the most effective dose and provide evidence that it is more effective in the context of moderate than severe pneumonitis. Mechanistically, LDLR at 1.0 Gy significantly suppressed bleomycin-induced accumulation of pulmonary interstitial macrophages, CD103+ dendritic cells and neutrophil-DC hybrids.

Item Type:Articles
Status:In Press
Refereed:Yes
Glasgow Author(s) Enlighten ID:Finney, Mr George and Stevenson, Mrs Katrina and Curley, Emer and Williams, Dr Karin and Strathdee, Mrs Karen and Rupp, Dr Angie and Jackson, Dr Mark and Chalmers, Professor Anthony and McSharry, Dr Charles
Authors: Jackson, M. R., Stevenson, K., Chahal, S. K., Curley, E., Finney, G. E., Gutierrez-Quintana, R., Onwubiko, E., Rupp, A., Strathdee, K., Williams, K., MacLeod, M. K.L., McSharry, C., and Chalmers, A. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:International Journal of Radiation Oncology, Biology, Physics
Publisher:Elsevier
ISSN:0360-3016
ISSN (Online):1879-355X
Published Online:31 August 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in International Journal of Radiation Oncology, Biology, Physics 2021
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
314690Generation of a unique Glasgow RadNet multimodality molecular imaging dataset measuring dynamic immunometabolic phenotypes during radiotherapy in mouse models of lung cancerDavid LewisCancer Research UK (CRUK)C16583/A28803Institute of Cancer Sciences
173895Investigating elevated DNA replication stress in glioblastoma stem cells and neural stem cells and exploiting its therapeutic potential.Ross CarruthersCancer Research UK (CRUK)C52808/A23920CS - Clinical Trials Research
302383Communication between lung immune and stromal cells drives tissue protective immune memoryMegan MacLeodWellcome Trust (WELLCOTR)210703/Z/18/ZIII - Immunology
300391Investigating the role of the actin-myosin regulatory protein MRCK in promoting radiation induced infiltration by glioblastoma cellsAnthony ChalmersMedical Research Council (MRC)MR/R009473/1CS - Clinical Trials Research