Institute of Cancer Sciences, University of Glasgow, United Kingdom.
Cancer Research UK Beatson Institute, Glasgow, United Kingdom.
Int J Radiat Oncol Biol Phys. 2022 Jan 1;112(1):197-211. doi: 10.1016/j.ijrobp.2021.08.029. Epub 2021 Aug 31.
Low-dose whole lung radiation therapy (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.
Female C57BL/6 mice were treated with intranasal bleomycin sulfate (7.5 or 11.25 units/kg, day 0) and then exposed to whole lung radiation therapy (0.5, 1.0, or 1.5 Gy, or sham; day 3). Bodyweight was measured daily, and lung tissue was harvested for histology and flow cytometry on day 10. Computed tomography lung imaging was performed before radiation (day 3) and pre-endpoint (day 10).
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 histopathologic lung changes. Mice experiencing moderate initial weight loss were more likely to respond to LDLR than those experiencing severe initial weight loss. In addition, LDLR (1.0 Gy) significantly reduced bleomycin-induced increases in interstitial macrophages, CD103+ dendritic cells (DCs), and neutrophil-DC hybrids. Overall, bleomycin-treated mice exhibited significantly higher percentages of nonaerated 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 radiologic readouts of bleomycin-induced pneumonitis.
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+ DCs, and neutrophil-DC hybrids.
低剂量全肺放射治疗（LDLR）已被提议用于治疗与 SARS-CoV-2 感染相关的急性呼吸窘迫综合征患者，并且正在进行临床试验。迫切需要临床前证据来证明这种方法的合理性，并确定剂量、时间表和作用机制。
雌性 C57BL/6 小鼠用鼻内硫酸博来霉素（7.5 或 11.25 单位/千克，第 0 天）处理，然后暴露于全肺放射治疗（0.5、1.0 或 1.5Gy 或假照射；第 3 天）。每天测量体重，并在第 10 天收获肺组织进行组织学和流式细胞术分析。在放射治疗前（第 3 天）和终点前（第 10 天）进行计算机断层扫描肺成像。
博来霉素导致严重程度不同的间质性肺炎，与体重减轻相关。1.0Gy 的 LDLR 与 98%的初始体重恢复的小鼠比例显著增加相关，并且这些小鼠中的一部分表现出较轻的组织病理学肺变化。经历中度初始体重减轻的小鼠比经历严重初始体重减轻的小鼠更有可能对 LDLR 有反应。此外，LDLR（1.0Gy）显著降低了博来霉素诱导的间质巨噬细胞、CD103+树突状细胞（DC）和中性粒细胞-DC 杂交体的增加。总体而言，博来霉素处理的小鼠的左肺比右肺表现出明显更高比例的非充气肺，并且 LDLR（1.0Gy）限制了右肺但不是左肺充气肺容积的进一步减少。0.5 和 1.5Gy 的 LDLR 不能改善博来霉素诱导的间质性肺炎的体重、流式细胞术或放射学读数。
我们的数据支持这样的概念，即 LDLR 可以改善急性炎症性肺损伤，确定 1.0Gy 为最有效剂量，并提供证据表明，在中度而非重度间质性肺炎的情况下，它更有效。在机制上，1.0Gy 的 LDLR 显著抑制了博来霉素诱导的肺间质巨噬细胞、CD103+DC 和中性粒细胞-DC 杂交体的积累。
Zotero 插件
