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. 2020 Aug 29;40(4):671–676. doi: 10.1007/s11596-020-2236-7

Targeted Antagonism of Vascular Endothelial Growth Factor Reduces Mortality of Mice with Acute Respiratory Distress Syndrome

Zhao Zhang 1, Dong-shi Lu 1, Dan-qing Zhang 1, Xin Wang 2, Yu Ming 3,✉, Zhou-yang Wu 1,✉
PMCID: PMC7456355  PMID: 32862377

Summary

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 PaO2 levels were normal in the PBS group, the blank group, and the control group. The LPS group and ARDS group showed significant hypoxia. PaO2 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.

Key words: acute respiratory distress syndrome, vascular endothelial growth factor, soluble fms-like tyrosine kinase-1, ultrasound microbubble, lipopolysaccharide

Conflict of Interest Statement

I declare on behalf of my co-authors and myself that we do not have any conflict of interest.

Footnotes

This study was supported by Scientific Research Fund of Hubei Provincial Department of Education (No. B2016081) and Young Scholar Research Grant of Chinese Anesthesiologist Association (No. 21700007).

Contributor Information

Zhao Zhang, Email: lyzzaaaa@126.com.

Yu Ming, Email: 497396197@qq.com.

Zhou-yang Wu, Email: wzy6638@hotmail.com.

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