Liu Ke-Yang, Yang Wen-Hui, Dong Xiao-Kai, Cong Li-Ming, Li Na, Li Yun, Wen Zhan-Bo, Yin Zhe, Lan Zhi-Jie, Li Wei-Peng, Li Jin-Song
1 Tongzhou Institute of Infectious Diseases and Epidemiology , Beijing, China .
2 State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology , Beijing, China .
J Aerosol Med Pulm Drug Deliv. 2016 Oct;29(5):393-405. doi: 10.1089/jamp.2015.1233. Epub 2016 Jan 8.
Lytic mycobacteriophage D29 has the potential for tuberculosis treatment including multidrug-resistant strains. The aims of this study are to investigate deposition and distribution of aerosolized phage D29 particles in naive Balb/C mice, together with pharmacokinetics and evaluation of acute lung injury.
Pharmacokinetics and BALF (bronchoalveolar lavage fluids) were analyzed after administration of phage D29 aerosols by endotracheal route using Penn-century aerosolizer; Collison 6-jet and Spinning top aerosol nebulizers (STAG) were used to generate phage aerosols with different particle size distributions in nose-only inhalation experiments. After exposure, deposited amounts of phage D29 particles in respiratory tracts were measured, and deposition efficiencies were calculated. A typical path deposition model for mice was developed, and then comparisons were made between predictions and experimentally measured results.
Approximately 10% of aerosolized phages D29 reached lung of mouse for pulmonary delivery, and were completely eliminated until 72 h after administration. In contrast, about 0.1% of intraperitoneal injected phages reached the lung, and were almost eliminated at 12 h time point. The inflammation was hardly observed in lung according to the results of BALF analysis. The CMADs (count median aerodynamic diameters) of generated aerosol by Collison and STAG nebulizer were 0.8 μm and 1.5 μm, respectively. After nose-only exposure, measured deposition efficiencies in whole respiratory tract for 0.8 and 1.5 μm phage particles were below 1% and 10%, respectively. Predictions of the computer deposition model compared fairly well with experimentally measured results.
This is the first systematic study of phage D29 aerosol respiratory challenge in laboratory animals. It provides evidence that aerosol delivery of phage D29 is an effective way for treating pulmonary infections caused by Mycobacterium tuberculosis. This research will also provide important data for future inhalation experiments.
裂解性分枝杆菌噬菌体D29具有治疗结核病（包括耐多药菌株）的潜力。本研究的目的是调查雾化噬菌体D29颗粒在未感染的Balb/C小鼠体内的沉积和分布情况，以及其药代动力学和急性肺损伤评估。
使用宾夕法尼亚世纪雾化器通过气管内途径给予噬菌体D29气雾剂后，分析其药代动力学和支气管肺泡灌洗液（BALF）；在仅经鼻吸入实验中，使用科里森6喷口雾化器和旋转顶部雾化器（STAG）产生具有不同粒径分布的噬菌体气雾剂。暴露后，测量呼吸道中噬菌体D29颗粒的沉积量，并计算沉积效率。建立了小鼠的典型路径沉积模型，然后将预测结果与实验测量结果进行比较。
约10%的雾化噬菌体D29到达小鼠肺部用于肺部给药，并在给药后72小时内完全清除。相比之下，约0.1%的腹腔注射噬菌体到达肺部，并在12小时时间点几乎被清除。根据BALF分析结果，肺部几乎未观察到炎症。科里森雾化器和STAG雾化器产生的气雾剂的计数中位空气动力学直径（CMAD）分别为0.8μm和1.5μm。仅经鼻暴露后，0.8μm和1.5μm噬菌体颗粒在整个呼吸道中的测量沉积效率分别低于1%和10%。计算机沉积模型的预测结果与实验测量结果相当吻合。
这是首次在实验动物中对噬菌体D29气雾剂呼吸道激发进行的系统研究。它提供了证据表明，噬菌体D29的气雾剂给药是治疗由结核分枝杆菌引起的肺部感染的有效方法。这项研究还将为未来的吸入实验提供重要数据。
