Sulodexide improves vascular permeability via glycocalyx remodelling in endothelial cells during sepsis

Jiayun Ying; Caiyan Zhang; Yaodong Wang; Tingyan Liu; Zhenhao Yu; Kexin Wang; Weiming Chen; Yufeng Zhou; Guoping Lu

doi:10.3389/fimmu.2023.1172892

Sulodexide improves vascular permeability via glycocalyx remodelling in endothelial cells during sepsis

Front Immunol. 2023 Aug 8:14:1172892. doi: 10.3389/fimmu.2023.1172892. eCollection 2023.

Authors

Jiayun Ying¹, Caiyan Zhang¹, Yaodong Wang¹, Tingyan Liu¹, Zhenhao Yu¹, Kexin Wang², Weiming Chen¹, Yufeng Zhou^{2

3

4}, Guoping Lu¹

Affiliations

¹ Department of Critical Care Medicine, Children's Hospital of Fudan University, Shanghai, China.
² Institute of Pediatrics, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
³ National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China.
⁴ State-level Reginal Children's Medical Center, Children's Hospital Of Fudan University at Xiamen (Xiamen Children's Hospital), Fujian Provincial Key Laboratory of Neonatal Diseases, Fujian, China.

Abstract

Background: Degradation of the endothelial glycocalyx is critical for sepsis-associated lung injury and pulmonary vascular permeability. We investigated whether sulodexide, a precursor for the synthesis of glycosaminoglycans, plays a biological role in glycocalyx remodeling and improves endothelial barrier dysfunction in sepsis.

Methods: The number of children with septic shock that were admitted to the PICU at Children's Hospital of Fudan University who enrolled in the study was 28. On days one and three after enrollment, venous blood samples were collected, and heparan sulfate, and syndecan-1 (SDC1) were assayed in the plasma. We established a cell model of glycocalyx shedding by heparinase III and induced sepsis in a mouse model via lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP). Sulodexide was administrated to prevent endothelial glycocalyx damage. Endothelial barrier function and expression of endothelial-related proteins were determined using permeability, western blot and immunofluorescent staining. The survival rate, histopathology evaluation of lungs and wet-to-dry lung weight ratio were also evaluated.

Results: We found that circulating SDC1 levels were persistently upregulated in the non-alive group on days 1 and 3 and were positively correlated with IL-6 levels. Receiver operating characteristic curve analysis showed that SDC1 could distinguish patients with mortality. We showed that SDC1-shedding caused endothelial permeability in the presence of heparinase III and sepsis conditions. Mechanistically, sulodexide (30 LSU/mL) administration markedly inhibited SDC1 shedding and prevented endothelial permeability with zonula occludens-1 (ZO-1) upregulation via NF-κB/ZO-1 pathway. In mice with LPS and CLP-induced sepsis, sulodexide (40 mg/kg) administration decreased the plasma levels of SDC1 and increased survival rate. Additionally, sulodexide alleviated lung injury and restored endothelial glycocalyx damage.

Conlusions: In conclusion, our data suggest that SDC1 predicts prognosis in children with septic shock and sulodexide may have therapeutic potential for the treatment of sepsis-associated endothelial dysfunction.

Keywords: Syndecan-1; endothelium barrier function; glycocalyx remodeling; sepsis; sulodexide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Body Weight
Capillary Permeability
Endothelial Cells
Glycocalyx
Glycosaminoglycans / pharmacology
Lipopolysaccharides
Lung Injury*
Mice
Sepsis* / drug therapy
Shock, Septic*

Substances

glucuronyl glucosamine glycan sulfate
Lipopolysaccharides
Glycosaminoglycans

Grants and funding

This work was supported by grants from the National Key R&D Program of China (2021YFC2701800 and 2021YFC2701805 to GL; 2021YFC2701802 to YZ), the National Natural Science Foundation of China (82241038, 81974248 to YZ, 82202374 to CZ), and the Shanghai Committee of Science and Technology (23ZR1407600, 21140902400, 21ZR1410000, 19ZR1406400 to YZ, and 22ZR1408500 to CZ).