Low-Dose Lung Radiation Therapy for COVID-19 Lung Disease: A Preclinical Efficacy Study in a Bleomycin Model of Pneumonitis

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.

Low-Dose Whole Lung Irradiation for Treatment of COVID-19 Pneumonia: A Systematic Review and Meta-Analysis

“…Also, in a preclinical bleomycininduced pneumonitis model, 1.5 Gy of WLI was shown to be incapable of reducing mice lung capacity deterioration as measured by CT scanning compared with 1 Gy dose. 35 Moreover, mice with moderate lung injury recovered significantly more than the severe pneumonitis cases. Also, in their second cohort, Hess et al 20 selected more favorable controls and excluded controls who experienced rapid clinical decline at admission, thus introducing an undeniable selection bias, which was probably the reason behind the lower mortality rate in this group.…”

Pulmonary Delivery of Hydroxychloroquine Nanostructured Lipid Carrier as a Potential Treatment of COVID-19

“…In the current study, the potential efficacy of the prepared HCQ-NLC was evaluated in BLM-induced acute lung injury, which is the most widely used model for studying the impact of drugs on the management of pulmonary injury [33]. BLM generates a wellestablished murine model of lung inflammation with pathophysiologic changes including the stimulation of cytokines in lung tissues likely similar to that of COVID-19 [34,35].…”

Impact of X-radiation in the management of COVID-19 disease

“…A recent study with nine clinical trials used the dose range between 0.5-1 Gy in a single fraction to investigate the effect of whole-lung irradiation of COVID-19 patients by analyzing the parameters such as CRP, IL-6, D- dimer, and ferritin as it can affect the lung macrophages at these doses[ 39 ]. The therapeutic benefits of LDRT for pneumonitis were evaluated based on the percentage of recovery and the extent of severity[ 41 ]. The most commonly evaluated outcome parameters were ventilator-free numerous hematologic, cardiac, hepatic, and inflammatory markers.…”