Protectin DX Relieve Hyperoxia‐induced Lung Injury by Protecting Pulmonary Endothelial Glycocalyx

Abstract

Background

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature infants with limited treatments and poor prognosis. Damaged endothelial glycocalyx leads to vascular permeability, lung edema and inflammation. However, whether hyperoxia increases neonatal pulmonary microvascular permeability by degrading the endothelial glycocalyx remains unknown.

Methods

Newborn mice were maintained in 60–70% O₂ for 7 days. Protectin DX (PDX), an endogenous lipid mediator, was injected intraperitoneally on postnatal d 0, 2, 4 and 6. Lung samples and bronchoalveolar lavage fluid were taken at the end of the study. Primary human umbilical vein endothelial cells (HUVECs) were cultured in 80%O₂.

Results

Hyperoxia exposure for 7 days led to neonatal mice alveolar simplification with less radial alveolar count (RAC), mean linear intercept (MLI) and mean alveolar diameter (MAD) compared to the control group. Hyperoxia exposure increased lung vascular permeability with more fluid and proteins and inflammatory factors, including TNF-α and IL-1β, in bronchoalveolar lavage fluid while reducing the heparan sulfate (HS), the most abundant component of the endothelial glycocalyx, in the pulmonary endothelial cells. PDX relieve these changes. PDX attenuated hyperoxia-induced high expression of heparanase (HPA), the endoglycosidase that shed endothelial glycocalyx, p‐P65, P65, and low expression of SIRT1. BOC‐2 and EX527 abolished the affection of PDX both in vivo and intro.

Conclusion

In summary, our findings indicate that PDX treatment relieves hyperoxia‐induced alveolar simplification, vascular leakage and lung inflammation by attenuating pulmonary endothelial glycocalyx injury via the SIRT1/NF‐κB/ HPA pathway.

Keywords:

• bronchopulmonary dysplasia
• endothelial glycocalyx
• inflammation
• protectin DX

Ethical Approval

All experiments were performed following the Guidelines for the Use of Experimental Animal Care issued by the National Institutes of Health and approved by the Experimental Ethics Committee of Wenzhou Medical University.

Acknowledgments

This study was funded by the Key R&D Program of Zhejiang Province (2019C03011), Wenzhou Science and Technology Project (Y20180092), Wenzhou Major Science and Technology Innovation Project (2018ZY006) and Clinical Research Foundation of the 2nd Affiliated Hospital of Wenzhou Medical University (SAHoWMU-CR2018-11-134).

Disclosure

The authors report no conflicts of interest in this work.