Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Senior Cadre, No. 989 Hospital, The Joint Logistics Support Force of the Chinese People's Liberation Army, Luoyang, 471003, China.
Curr Med Sci. 2020 Aug;40(4):671-676. doi: 10.1007/s11596-020-2236-7. Epub 2020 Aug 29.
Acute respiratory distress syndrome (ARDS) is associated with a mortality of 45%. Our previous research indicated that anti-vascular endothelial growth factor (VEGF) could maintain the normal structure and function of the respiratory barrier. However, systemic application of VEGF antagonists would lead to animal death. This study attempts to study the targeted drug delivery for ARDS. In this study, we used soluble fms-like tyrosine kinase-1 (sFlt)-targeted ultrasound microbubbles to antagonize the effect of VEGF on lung tissue. Ninety male BALB/c mice were randomly assigned to 6 groups: phosphate buffer saline (PBS) group (PBS+PBS); blank group (PBS+empty microbubbles); lipopolysaccharide (LPS) group (LPS+PBS); ARDS group (LPS+empty microbubbles); control group (PBS+sFlt microbubbles); and treatment group (LPS+sFlt microbubbles). After administration of LPS or PBS in the corresponding groups, the sFlt-targeted microbubbles or empty microbubbles were injected into the blood circulation. Then the lungs were irradiated with ultrasound, which ruptured the drug-loaded microbubbles and helped release drugs to the lung tissues targeted. The lung injury score, lung wet/dry ratio (W/D), liver and kidney functions, and the mortality of the mice in all groups were investigated at the predetermined time point. The difference in mortality between groups was examined by Fisher test. Other data were analyzed by one-way analysis of variance (ANOVA). A value of P<0.05 indicates that the difference was significant. The results showed that the PaO levels were normal in the PBS group, the blank group, and the control group. The LPS group and ARDS group showed significant hypoxia. PaO was improved significantly in the treatment group. The lung injury score and W/D were normal in the PBS group, the blank group, and the control group. The lung injury score and W/D increased significantly in the LPS group and ARDS group and decreased in the treatment group (P<0.05). The mortality rate of the ARDS model was 60% (95% confidence interval 47.5%-72.5%), and that with sFlt-targeted microbubbles was significantly lower at only 40% (95% confidence interval 27.5%-52.5%, P<0.05). It was concluded that anti-VEGF with sFlt targeted ultrasound microbubbles attenuated the lung injury and ultimately reduced the 7-day mortality effectively. It might be a suitable therapeutic tool for the treatment of ARDS.
急性呼吸窘迫综合征 (ARDS) 的死亡率为 45%。我们之前的研究表明，抗血管内皮生长因子 (VEGF) 可以维持呼吸屏障的正常结构和功能。然而，全身应用 VEGF 拮抗剂会导致动物死亡。本研究试图探讨 ARDS 的靶向药物递送。在这项研究中，我们使用可溶性 fms 样酪氨酸激酶-1 (sFlt)-靶向超声微泡来拮抗 VEGF 对肺组织的作用。90 只雄性 BALB/c 小鼠被随机分为 6 组：磷酸盐缓冲盐水 (PBS) 组 (PBS+PBS)；空白组 (PBS+空微泡)；脂多糖 (LPS) 组 (LPS+PBS)；ARDS 组 (LPS+空微泡)；对照组 (PBS+sFlt 微泡)；和治疗组 (LPS+sFlt 微泡)。在相应组给予 LPS 或 PBS 后，将 sFlt 靶向微泡或空微泡注入血液循环。然后用超声照射肺部，使载药微泡破裂，有助于将药物靶向释放到肺部组织。在预定时间点检测各组小鼠的肺损伤评分、肺湿/干重比 (W/D)、肝肾功能及死亡率。采用 Fisher 检验比较组间死亡率差异。其他数据采用单因素方差分析 (ANOVA) 进行分析。P<0.05 表示差异有统计学意义。结果显示，PBS 组、空白组和对照组的 PaO 水平正常，LPS 组和 ARDS 组出现明显低氧血症，治疗组 PaO 明显改善。PBS 组、空白组和对照组的肺损伤评分和 W/D 正常，LPS 组和 ARDS 组的肺损伤评分和 W/D 明显升高，治疗组降低 (P<0.05)。ARDS 模型的死亡率为 60%(95%置信区间 47.5%-72.5%)，而 sFlt 靶向微泡组的死亡率显著降低至 40%(95%置信区间 27.5%-52.5%，P<0.05)。结论：抗 VEGF 与 sFlt 靶向超声微泡减轻肺损伤，最终有效降低 7 天死亡率，可能成为治疗 ARDS 的一种合适的治疗工具。
